@article {pmid42917927,
year = {2026},
author = {Mastnak-Sokolov, P and Košak, U and Meden, A and Knez, D and Žakelj, S and Horvat, S and Pišlar, A and Kljun, J and Igert, A and Dias, J and Nachon, F and Brazzolotto, X and Novak, M and Rydlova, V and Karasova, JZ and Soukup, O and Manik, A and Detka, J and Sałat, K and Gobec, S},
title = {Structure-Guided Design of a Brain-Penetrant Covalent Inhibitor of Human Butyrylcholinesterase with In Vivo Procognitive Efficacy.},
journal = {Journal of medicinal chemistry},
volume = {69},
number = {19},
pages = {22506-22538},
doi = {10.1021/acs.jmedchem.6c01737},
pmid = {42917927},
issn = {1520-4804},
support = {DZRO-FVZ22-ZHN II//Ministerstvo Obrany České Republiky/ ; P1-0175//Javna Agencija za Raziskovalno Dejavnost RS/ ; P1-0208//Javna Agencija za Raziskovalno Dejavnost RS/ ; //Fakultní nemocnice Hradec Králové/ ; DGA/SSA NBC-5-C-2316//Service de Santé des Armées/ ; DEC-2021/43/I/NZ7/00342//Narodowe Centrum Nauki/ ; DGA/SSA NBC-5-C-2316//Direction Générale de l'Armement/ ; SN-ZRD/22-27/0510//Univerza v Ljubljani/ ; },
mesh = {Humans ; *Butyrylcholinesterase/metabolism/chemistry ; Animals ; *Cholinesterase Inhibitors/pharmacology/chemistry/metabolism/chemical synthesis/pharmacokinetics/therapeutic use ; *Brain/metabolism/drug effects ; *Drug Design ; Mice ; Crystallography, X-Ray ; Structure-Activity Relationship ; *Pyrrolidines/pharmacology/chemistry ; Models, Molecular ; Male ; *Carbamates/pharmacology/chemistry ; *Nootropic Agents/pharmacology/chemistry/chemical synthesis/pharmacokinetics ; Scopolamine ; },
abstract = {Butyrylcholinesterase (BChE) has emerged as a validated therapeutic target for the management of Alzheimer's disease symptoms, particularly in advanced stages when acetylcholinesterase activity declines. Despite the numerous BChE inhibitors reported, only the cymserine derivative bisnorcymserine has progressed to clinical evaluation. Here, we report the design and characterization of a novel selective human BChE (hBChE) inhibitor, N-benzylpyrrolidine carbamate (S)-(+)-14. Kinetic analyses and X-ray crystallography of the hBChE-inhibitor complex confirm a covalent mechanism of inhibition. Compound (S)-(+)-14 demonstrates favorable metabolic stability and achieves brain exposure following intraperitoneal administration in mice. In a scopolamine-induced cognitive impairment model, (S)-(+)-14 improves cognitive performance without causing cholinergic adverse effects or motor deficits. Collectively, these findings identify (S)-(+)-14 as a structurally validated, brain-penetrant covalent hBChE inhibitor and highlight its promise as a lead compound for the treatment of Alzheimer's disease.},
}

Humans
*Butyrylcholinesterase/metabolism/chemistry
Animals
*Cholinesterase Inhibitors/pharmacology/chemistry/metabolism/chemical synthesis/pharmacokinetics/therapeutic use
*Brain/metabolism/drug effects
*Drug Design
Mice
Crystallography, X-Ray
Structure-Activity Relationship
*Pyrrolidines/pharmacology/chemistry
Models, Molecular
Male
*Carbamates/pharmacology/chemistry
*Nootropic Agents/pharmacology/chemistry/chemical synthesis/pharmacokinetics
Scopolamine

@article {pmid42918387,
year = {2026},
author = {Verma, A and Goyal, A and Agrawal, N and Yadav, HN},
title = {Cellular senescence in ageing and neurodegenerative disorders: Molecular mechanisms, biomarkers, and therapeutic strategies.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111985},
doi = {10.1016/j.pnpbp.2026.111985},
pmid = {42918387},
issn = {1878-4216},
abstract = {Cellular senescence has been increasingly associated with neurodegenerative disorders, potentially linking ageing-related cellular impairment with mitochondrial dysfunction, chronic inflammation, and disrupted intercellular signalling. The present study aims to explore the increasing relevance of cellular senescence among key cell types, including neurons, astrocytes, neural progenitor cells, microglia and oligodendrocyte-lineage cells across neurodegenerative ailments such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. This review discusses the findings of pre-clinical and clinical studies which suggest that senescence-associated features may contribute to neurodegeneration. Further, it provides an overview of the biomarkers used in the identification of senescence in the CNS. Also, the review examines senotherapeutic treatment approaches, highlighting their actions on different CNS cell types and the growing clinical evidence. It also points out the challenges in translating these approaches to clinical application, such as targeting specific cell types and the lack of suitable biomarkers. Collectively, present findings suggest that senescence-associated alterations may contribute to neurodegeneration, although their effects appear to vary across cell types and diseases.},
}

@article {pmid42911381,
year = {2026},
author = {Chen, Y and Tong, Z and Wang, H and Xu, X and Chen, Q and Lu, J and Hu, Y and Zhang, X and Zhao, H and Chen, J and Zhang, B},
title = {Dynamic long-term modulation of cognition, brain structure and covariance networks in mild cognitive impairment due to AD by donepezil: A 36-month longitudinal study.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42911381},
issn = {1432-1459},
support = {82330059//Innovative Research Group Project of the National Natural Science Foundation of China/ ; 82271965//Innovative Research Group Project of the National Natural Science Foundation of China/ ; 2023-LCYJ-MS11//Nanjing Drum Tower Hospital/ ; XJSFZLX202333//Nanjing Drum Tower Hospital/ ; RC2022-023//Nanjing Drum Tower Hospital/ ; BE2022679//Jiangsu Provincial Key Research and Development Program/ ; },
mesh = {Humans ; *Donepezil/pharmacology/therapeutic use ; Female ; Male ; Longitudinal Studies ; *Cognitive Dysfunction/drug therapy/etiology/pathology/diagnostic imaging ; *Alzheimer Disease/drug therapy/complications/pathology/diagnostic imaging ; Aged ; Cross-Sectional Studies ; Magnetic Resonance Imaging ; *Brain/drug effects/pathology/diagnostic imaging ; *Nootropic Agents/pharmacology/therapeutic use ; Retrospective Studies ; Disease Progression ; *Nerve Net/drug effects/diagnostic imaging/pathology ; Cognition/drug effects ; Cognitive Enhancement ; Middle Aged ; },
abstract = {BACKGROUND: Whether donepezil exerts long-term efficacy in mitigating cognitive decline, preserving brain structure, and restoring impaired structural covariance networks in patients with mild cognitive impairment due to Alzheimer's disease (AD-MCI) remains controversial.

OBJECTIVE: This study aimed to characterize the longitudinal dynamic alterations in cognition, brain morphology, and structural covariance network topology in AD-MCI patients receiving continuous 36-month donepezil treatment, thereby elucidating the long-term modulatory effects of donepezil on AD progression.

METHODS: Cross-sectional analysis included 92 normal controls (NC) and 107 AD-MCI patients to identify baseline abnormalitiesin cognitive performance, brain morphological parameters, global topological features, and nodal metrics of individual gray matter covariance networks. Subsequently, 35 AD-MCI patients who completed 36-month continuous donepezil treatment were retrospectively enrolled to explore the therapeutic modulation of donepezil on the aforementioned abnormal indicators. Linear and piecewise linear mixed-effects models were employed to quantify longitudinal changes.

RESULTS: AD-MCI patients showed left hippocampus (including subfields) atrophy and widespread structural covariance network impairment at baseline. During treatment, significant time main effects were observed in MMSE scores and the volume of the left hippocampus and multiple subfields, both of which continued to show progressive decline, with accelerated deterioration between 12 and 18 months. Global topological metrics stabilized after initial short-term improvement, while right hippocampus nodal metrics were significantly enhanced.

CONCLUSIONS: Donepezil treatment in AD-MCI patients represents a dynamic therapeutic process: it elicits transient short-term improvement of global brain network topology but confers only modest long-term benefits, with insufficient evidence supporting sustained, impactful neuroprotective effects. This study provides novel multi-level longitudinal evidence describing the neuroimaging changes underlying donepezil's modulation of AD progression.},
}

Humans
*Donepezil/pharmacology/therapeutic use
Female
Male
Longitudinal Studies
*Cognitive Dysfunction/drug therapy/etiology/pathology/diagnostic imaging
*Alzheimer Disease/drug therapy/complications/pathology/diagnostic imaging
Aged
Cross-Sectional Studies
Magnetic Resonance Imaging
*Brain/drug effects/pathology/diagnostic imaging
*Nootropic Agents/pharmacology/therapeutic use
Retrospective Studies
Disease Progression
*Nerve Net/drug effects/diagnostic imaging/pathology
Cognition/drug effects
Cognitive Enhancement
Middle Aged

@article {pmid42911727,
year = {2026},
author = {Tojo, T and Itoh, Y and Kurohara, T and Li, Y and Singh, R and Narozny, R and van der Wiel, AMA and Furutani, R and Miyake, Y and Yamashita, Y and Kusuhara, H and Kanamitsu, K and Horiguchi, N and Ono, H and Kusakabe, KI and Uchida, S and Suzuki, T},
title = {Discovery of an HDAC2-Selective Inhibitor via Enzyme-Inhibitor-Binding Thermodynamics/Kinetics as a Prospective Neurological Disorder Drug.},
journal = {Journal of medicinal chemistry},
volume = {69},
number = {20},
pages = {23368-23386},
doi = {10.1021/acs.jmedchem.5c03068},
pmid = {42911727},
issn = {1520-4804},
support = {//Takeda Science Foundation/ ; 22ama121041j0001//Japan Agency for Medical Research and Development/ ; JP24ak0101197h0002//Japan Agency for Medical Research and Development/ ; JP24ama121051//Japan Agency for Medical Research and Development/ ; JP24ama121053//Japan Agency for Medical Research and Development/ ; JP24zf0127010//Japan Agency for Medical Research and Development/ ; JP25zf0127010//Japan Agency for Medical Research and Development/ ; //Uehara Memorial Foundation/ ; 22H02220//Japan Society for the Promotion of Science/ ; 24H00595//Japan Society for the Promotion of Science/ ; 25K03035//Japan Society for the Promotion of Science/ ; 2025-//Nanken/ ; kokunai//Nanken/ ; 47//Nanken/ ; JPMJCR14L2//Core Research for Evolutional Science and Technology/ ; //Ministry of Education, Culture, Sports, Science and Technology/ ; JPMXP1323015483//Institute of Science Tokyo/ ; //Mochida Memorial Foundation for Medical and Pharmaceutical Research/ ; },
mesh = {Animals ; Thermodynamics ; Humans ; *Histone Deacetylase Inhibitors/pharmacology/chemistry/therapeutic use/metabolism ; *Histone Deacetylase 2/antagonists & inhibitors/metabolism/chemistry ; Mice ; Kinetics ; Drug Discovery ; Crystallography, X-Ray ; Structure-Activity Relationship ; Models, Molecular ; Protein Binding ; },
abstract = {In this study, we identified KTT-1 (12) as an HDAC2-selective inhibitor through in vitro evaluations based on both thermodynamics and kinetics of the enzyme-inhibitor binding. This approach stands in sharp contrast to conventional drug discovery research, which usually focuses only on thermodynamics. An X-ray crystallography study on HDAC2 complexed with 12 in combination with quantum chemical calculations on model compounds suggested that the 2-furanyl group of 12 contributes to the selective HDAC2 inhibition. In our cellular assays, 12 preferentially inhibited HDAC2 over its highly homologous HDAC1 and promoted neurite outgrowth of neuro-2a cells. Furthermore, treatment of mice with 12 improved the memory and depression-like behavior of stress-vulnerable mice. The results indicate that 12 is a promising lead compound for neurological disorders such as Alzheimer's disease and depression and demonstrate that inhibitor evaluations that combine enzyme-inhibitor-binding thermodynamics and kinetics are useful tools for drug discovery research.},
}

Animals
Thermodynamics
Humans
*Histone Deacetylase Inhibitors/pharmacology/chemistry/therapeutic use/metabolism
*Histone Deacetylase 2/antagonists & inhibitors/metabolism/chemistry
Mice
Kinetics
Drug Discovery
Crystallography, X-Ray
Structure-Activity Relationship
Models, Molecular
Protein Binding

@article {pmid42911957,
year = {2026},
author = {Dahle, S and Einevoll, GT and Ness, TV},
title = {Cell-type dependence of effects from transcranial electric brain stimulation.},
journal = {PLoS computational biology},
volume = {22},
number = {10},
pages = {e1014895},
doi = {10.1371/journal.pcbi.1014895},
pmid = {42911957},
issn = {1553-7358},
abstract = {There is an urgent need for better treatment options for many neurological conditions, including Alzheimer's disease, Parkinson's disease, depression, and epilepsy. Transcranial electrical stimulation (tES) is a non-invasive, safe, inexpensive, and promising method that could address some of this unmet need. The therapeutic value of tES has been well demonstrated, but the effect is highly variable. To enable tES to reach its full potential requires a better understanding of how tES modulates neural activity so that tES treatments can be tailored to specific neurological conditions and individual patients. The neural response to tES is, however, highly complex, and the parameter space involved in optimizing tES treatments is daunting. This has made it difficult to obtain general insights into how tES modulates neural activity, and a central challenge lies in the cell-type-specific and frequency-dependent nature of these responses. In this study, we investigated cell-type-specific neuronal responses to tES over a broad frequency range, using a large database of biophysically detailed neuron models. We found that pyramidal cells respond strongly to low-frequency tES, but their responses drop sharply with frequency. In contrast, inhibitory neurons show a smaller reduction and, on average, become more responsive than pyramidal cells above ~60 Hz. By leveraging a reciprocity theorem we demonstrated that the effect of tES on a given cell-type is proportional to the frequency-dependent current-dipole moment that determines the EEG-signal contribution of this cell-type. We further identified the dendritic asymmetry as key in determining tES responses across the frequency spectrum. Counterintuitively, we also found that while total cell length increases tES sensitivity at low frequencies, it can have the opposite effect at high frequencies. Furthermore, we derived an analytical formula for idealized neuron models which can approximately predict the tES sensitivity of different cell types at any given frequency. By characterizing the role of morphology and stimulation frequency in determining tES responses of single cells, this is an important step towards a better understanding of tES at the fundamental level. These results also provide an efficient and accurate method for characterizing and comparing the tES responses of different neural populations across the frequency spectrum, which facilitates optimizing tES for cell-type specific targeting.},
}

@article {pmid42912549,
year = {2026},
author = {Guo, Y and Ji, Q and Yang, Y and Liang, M and Wu, Z},
title = {Amyloid PET Changes During Lecanemab Treatment in Patients With and Without Amyloid-related Imaging Abnormalities.},
journal = {Clinical nuclear medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/RLU.0000000000006726},
pmid = {42912549},
issn = {1536-0229},
abstract = {Lecanemab reduces cerebral amyloid-β burden in Alzheimer disease, but whether amyloid-related imaging abnormalities (ARIA) are associated with greater amyloid clearance remains unclear. We report 3 patients with comparable clinical backgrounds and similar baseline cognitive performance who underwent amyloid-β PET before and after lecanemab treatment. Quantitative analysis using Centiloid showed a greater reduction in amyloid burden in the patient who developed ARIA than in the 2 patients without ARIA. These observations suggest ARIA may be associated with more pronounced treatment-related amyloid clearance, warranting further investigation in larger cohorts.},
}

@article {pmid42913299,
year = {2026},
author = {Nakamae, MYT and Rivero-Jerez, PS and Butera, AP and Macedo, F},
title = {NMR characterization of Tacrine in aqueous solution and insights into its interaction with amyloid-β1-40 aggregates revealed by STD.},
journal = {Biophysical chemistry},
volume = {340},
number = {},
pages = {107722},
doi = {10.1016/j.bpc.2026.107722},
pmid = {42913299},
issn = {1873-4200},
abstract = {The deposition of β-amyloid peptide (Aβ) aggregates in the brain is widely accepted as one of the major factors driving the development of Alzheimer's disease (AD). Tacrine (9-amino-1,2,3,4-tetrahydroacridine) is one of the most potent acetylcholinesterase inhibitors approved for the symptomatic treatment of AD, but its clinical use was discontinued due to hepatotoxicity. Recent studies have reported that tacrine can interact with Aβ and inhibit its aggregation, although the underlying mechanism is not yet fully elucidated, highlighting the need for detailed spectroscopic characterization under physiologically relevant conditions. Here, we report, to the best of our knowledge, the first complete and unambiguous assignment of the [1]H and [13]C NMR resonances of tacrine in aqueous solution at near-physiological pH using a combination of ROESY, HSQC, and HMBC experiments. pH-dependent [1]HNMR studies revealed that aromatic proton resonances are highly sensitive to protonation state, displaying pronounced but fully reversible chemical-shift variations. The resulting spectral map provides a reliable basis for ligand-observed NMR investigations of tacrine and related compounds in aqueous media. Moreover, saturation transfer difference (STD)-NMR experiments were optimized to investigate the interaction of tacrine with soluble Aβ1-40 aggregates. Under the optimized conditions, clear STD effects were observed exclusively in the presence of Aβ1-40, confirming direct ligand-aggregate interaction. Differential saturation transfer among aromatic protons, particularly for H-7, suggests distinct proximity relationships within the tacrine- Aβ1-40 complex. Together, these results establish a robust spectroscopic and methodological framework for future NMR studies of tacrine-based ligands and their interactions with amyloid assemblies.},
}

@article {pmid42913321,
year = {2026},
author = {Xu, W and Liu, M and Yu, X and Hao, Y and Fu, Z and Jin, L and Liang, H and Liao, K and Wang, X and Xu, J},
title = {Multi-omics analysis of potential therapeutic targets for Alzheimer's disease and associated differences in immune cell infiltration.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {24},
number = {1},
pages = {e01092},
doi = {10.1016/j.neurot.2026.e01092},
pmid = {42913321},
issn = {1878-7479},
abstract = {Alzheimer's disease (AD) represents a progressive neurodegenerative disorder that predominantly impairs the central nervous system. This study integrated single-cell RNA sequencing (scRNA-seq) and Mendelian randomization (MR) analysis to explore AD therapeutic targets and characterize alterations in immune cell infiltration and function. We analyzed the subtypes, developmental trajectories and intercellular communication of peripheral blood T cells from AD scRNA-seq data. Cell clustering identified CD8[+] T cells as the key immune subpopulation in AD, with two vital intercellular communication pathways (MIF-(CD74[+]CD44) and MIF-(CD74[+]CXCR4)) identified by trajectory analysis. The expression quantitative trait loci (eQTL) data retrieved from the IEU OpenGWAS database were utilized to perform MR and colocalization analysis to evaluate the association between target genes and AD. Six multiple-SNP and one single-SNP potential target genes were screened via differential expression and MR analysis. Among these, dual-specificity phosphatase 2 (DUSP2) showed a suggestive but weak association with AD, with a mild positive correlation observed in sensitivity analyses. No statistically significant shared genetic signals were detected via colocalization analysis. Additionally, significant differences in intercellular communication were observed between DUSP2+IM and DUSP2-IM cells, with distinct activity across various communication pathways. Gene expression levels in the AD group were significantly higher than in healthy individuals (P = 0.01). In conclusion, this study identified CD8[+] T cells as crucial factors in AD pathogenesis, while DUSP2 emerged as a suggestive candidate gene requiring further validation, providing novel mechanistic insights and potential therapeutic targets for AD treatment.},
}

@article {pmid42913372,
year = {2026},
author = {Tian, W and He, S and Wang, T and Zhong, S and Sun, J and Chen, J and Wang, X and Du, C and You, Y and Lin, Y and Wang, Y and Wang, G and Li, X and Chen, H},
title = {Spiro-Polycyclic Polyprenylated Acylphloroglucinols from Hypericum monogynum and Their anti-Alzheimer's Disease Effects.},
journal = {Journal of natural products},
volume = {89},
number = {9},
pages = {2486-2501},
doi = {10.1021/acs.jnatprod.6c00583},
pmid = {42913372},
issn = {1520-6025},
support = {2025XKJC0107//Qilu University of Technology/ ; 32270415//National Natural Science Foundation of China/ ; 2024J01042//Natural Science Foundation of Fujian Province/ ; },
mesh = {*Alzheimer Disease/drug therapy ; Animals ; Zebrafish ; *Phloroglucinol/pharmacology/chemistry/isolation & purification/analogs & derivatives ; *Hypericum/chemistry ; Molecular Structure ; Cholinesterase Inhibitors/pharmacology/chemistry ; *Spiro Compounds/chemistry/pharmacology/isolation & purification ; Humans ; Crystallography, X-Ray ; },
abstract = {Eight undescribed spiro-polycyclic polyprenylated acylphloroglucinols (PPAPs) with a 6/6/5 tricyclic architecture (1-8), together with eight known analogues (9-16), were isolated from Hypericum monogynum L. Their structures including absolute configurations were elucidated by spectroscopic analysis, single-crystal X-ray diffraction, and quantum chemical calculations. Biological evaluation revealed that compounds 4 and 16 showed potential as dual-target anti-Alzheimer's disease (AD) lead compounds, as they not only exhibited potent acetylcholinesterase (AChE) inhibitory activities but also induced peroxisome proliferator-activated receptor-γ transactivation and upregulated ATP-binding cassette transporter A1 expression. The in vivo anti-AD effects of 4 and 16 were evaluated by the zebrafish behavioral experiments. Compound 16 exhibited anti-AD effects with no detectable toxicity or teratogenicity, whereas 4 exhibited toxicity to zebrafish at 10 μM. These findings not only expand the chemical diversity of spiro-PPAPs but also underscore their potential as dual-target agents for AD treatment.},
}

*Alzheimer Disease/drug therapy
Animals
Zebrafish
*Phloroglucinol/pharmacology/chemistry/isolation & purification/analogs & derivatives
*Hypericum/chemistry
Molecular Structure
Cholinesterase Inhibitors/pharmacology/chemistry
*Spiro Compounds/chemistry/pharmacology/isolation & purification
Humans
Crystallography, X-Ray

@article {pmid42913958,
year = {2026},
author = {Luo, H and Qi, X and Liu, R and Xu, Z and Liu, Y and Wu, B},
title = {Utilization of Dental Preventive and Treatment Services Among Older Adults with and without ADRD.},
journal = {American journal of preventive medicine},
volume = {},
number = {},
pages = {108612},
doi = {10.1016/j.amepre.2026.108612},
pmid = {42913958},
issn = {1873-2607},
abstract = {INTRODUCTION: Individuals with Alzheimer's disease and related dementias (ADRD) face substantial challenges in accessing dental care, yet the types of services received and how they compare with peers without ADRD remain understudied. This study compared dental service utilization and procedure types between older adults with and without ADRD.

METHODS: A cross-sectional analysis was conducted in 2026 using 2017-2023 Medical Expenditure Panel Survey (MEPS) data for community-dwelling adults aged 65 years and older (N=35,538). Outcomes were any dental visit in the past year and receipt of preventive or treatment-based procedures among those with at least one visit. Survey-weighted logistic regression models estimated associations between ADRD status and each outcome. Blinder-Oaxaca decomposition partitioned the disparity in dental visits into an endowments component (the share explained by group differences in measured characteristics) and a coefficients component (the share reflecting differences in how those characteristics relate to care use).

RESULTS: Older adults with ADRD were less likely to have a dental visit (AOR=0.75, 95% CI: 0.64-0.88), and among those with a visit, less likely to receive preventive care (AOR=0.69, 95% CI: 0.50-0.95). No significant differences were observed in treatment-based procedures after adjustment. The disparity in dental visits (13 percentage points, p <0.001) was explained by both differences in characteristics (43.2%) and differences in coefficients (43.5%). Health status and education were the largest contributors to the explained component, while family income primarily drove the unexplained component. Disparities in preventive care were smaller (approximately 9 percentage points) and largely driven by the unexplained component.

CONCLUSIONS: Disparities in dental care for older adults with ADRD are associated with differences in individual characteristics as well as unexplained factors that may represent barriers to accessing dental care. Closing these gaps requires moving beyond financial coverage toward integrated, community-based delivery models. Such strategies are vital to shifting care from episodic treatment to sustainable prevention.},
}

@article {pmid42915464,
year = {2026},
author = {Huang, X and Ma, S and Li, X and Pan, J},
title = {Rationally Designed Peptides and Peptoids as Inhibitors of Amyloid-β (Aβ) Aggregation.},
journal = {Bioconjugate chemistry},
volume = {37},
number = {9},
pages = {1739-1770},
doi = {10.1021/acs.bioconjchem.6c00145},
pmid = {42915464},
issn = {1520-4812},
support = {22507040//National Natural Science Foundation of China/ ; 2024AFB782//Natural Science Foundation of Hubei Province/ ; B2024278//Scientific Research Program of the Hubei Provincial Department of Education/ ; },
mesh = {*Amyloid beta-Peptides/antagonists & inhibitors/metabolism/chemistry ; *Peptoids/chemistry/pharmacology/therapeutic use ; Humans ; *Drug Design ; *Peptides/chemistry/pharmacology/therapeutic use ; Alzheimer Disease/drug therapy/metabolism ; Animals ; *Protein Aggregates/drug effects ; },
abstract = {Peptide and peptoid are two types of peptidomimetics can be used as drugs for diseases. One of the main hallmarks in Alzheimer's Disease (AD) is Aβ aggregation. Due to the natural affinity between peptide and Aβ proteins, peptide therapeutics are found out to be suitable for the disease, as they are almost nontoxic, possess good biocompatibility and are structurally changeable. This review mainly focuses on peptide and peptoid as inhibitors targeting Aβ protein, elaborating on their design strategies and some of their inhibitory effects, providing diverse potential compounds for the treatment of AD. The involved peptide inhibitors are classified into three major categories based on their structural features: inhibitors based on the natural Aβ sequence, inhibitors based on non-natural Aβ sequences, and inhibitors conjugated with small molecule compounds. To facilitate understanding of the development process of each type of inhibitor, we have expounded on each major category in terms of chronological order, specialty and importance. It also summarized the challenges and design strategies faced by peptide inhibitors in targeting Aβ aggregation. This review provides a valuable resource for researchers in the field of synthetic peptide and their biomedical applications, offering structural insights into the design of new peptide for better diagnosis and therapeutic applications.},
}

*Amyloid beta-Peptides/antagonists & inhibitors/metabolism/chemistry
*Peptoids/chemistry/pharmacology/therapeutic use
Humans
*Drug Design
*Peptides/chemistry/pharmacology/therapeutic use
Alzheimer Disease/drug therapy/metabolism
Animals
*Protein Aggregates/drug effects

@article {pmid42915573,
year = {2026},
author = {Singh, S and Singh, SK},
title = {The "Glyco-Remodeling" Hypothesis in Alzheimer's Disease: Linking Protein N-Glycosylation to Pathogenesis and Translation.},
journal = {ACS chemical neuroscience},
volume = {17},
number = {18},
pages = {3252-3271},
doi = {10.1021/acschemneuro.6c00166},
pmid = {42915573},
issn = {1948-7193},
support = {1102015//Ministry of Education, India/ ; 21011503//Indian Institute of Technology (BHU) Varanasi/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; Glycosylation ; Animals ; Amyloid beta-Protein Precursor/metabolism ; Protein Processing, Post-Translational/physiology ; *Brain/metabolism/pathology ; tau Proteins/metabolism ; Membrane Glycoproteins/metabolism ; Receptors, Immunologic/metabolism ; Apolipoproteins E/metabolism ; },
abstract = {Alzheimer's disease (AD), an age-associated neurodegenerative disorder characterized by cognitive decline and accumulation of amyloid-β (Aβ) plaques and tau tangles, has long been studied through the lens of protein aggregation and phosphorylation. However, emerging evidence suggests that aberrant protein N-glycosylation, a key post-translational modification governing protein folding, trafficking, and signaling, plays an equally pivotal role in AD pathogenesis. This review consolidates current knowledge on N-glycosylation, and very briefly about the prominent O-Glycosylation dynamics in the healthy and diseased brain, with a focus on six key proteins amyloid precursor protein, immunoglobulin G (IgG), triggering receptor expressed on myeloid cells-2 (TREM2), tau (τ), apolipoprotein E, and transferrin whose altered glycosylation patterns perturb amyloidogenic processing, tau aggregation, microglial activity, lipid transport, and systemic immune balance. We introduce the glyco-remodeling hypothesis, proposing that stage-specific glycosylation changes act as molecular "remodeling" driving the progression from normal aging, to mild cognitive impairment, and ultimately AD. Framing AD through this lens positions glycans as both markers and modulators of disease progression, with direct implications for biomarker discovery, therapeutic targeting, and systems-level integration across aging and neurodegeneration.},
}

*Alzheimer Disease/metabolism/pathology
Humans
Glycosylation
Animals
Amyloid beta-Protein Precursor/metabolism
Protein Processing, Post-Translational/physiology
*Brain/metabolism/pathology
tau Proteins/metabolism
Membrane Glycoproteins/metabolism
Receptors, Immunologic/metabolism
Apolipoproteins E/metabolism

@article {pmid42916114,
year = {2026},
author = {Milardi, D and Han, J and Lee, HJ and Ding, F and Miller, Y and Faller, P and Bush, AI and Crouch, PJ and Finkelstein, DI and Double, KL and Jeremic, A and Lim, MH and Ramamoorthy, A},
title = {Metal Ions and Protein Aggregation: Unraveling Molecular Interactions and Theranostic Prospects in Proteinopathies.},
journal = {Chemical reviews},
volume = {126},
number = {18},
pages = {10249-10333},
doi = {10.1021/acs.chemrev.5c00420},
pmid = {42916114},
issn = {1520-6890},
support = {R01AG048934/AG/NIA NIH HHS/United States ; R35GM13973/GM/NIGMS NIH HHS/United States ; R35GM145409/GM/NIGMS NIH HHS/United States ; R01DK132214/DK/NIDDK NIH HHS/United States ; NA//Florida State University/ ; NA//National High Magnetic Field Laboratory/ ; 2022PAAYZE//NextGenerationEU/ ; CUP: B53D23016440006//NextGenerationEU/ ; DP230101031//Australian Research Council/ ; GNT1194028//National Health and Medical Research Council/ ; GNT2019931//National Health and Medical Research Council/ ; RS-2022-NR070709//National Research Foundation of Korea/ ; RS-2022-NR073879//National Research Foundation of Korea/ ; RS-2024-00353015//National Research Foundation of Korea/ ; RS-2024-00411134//National Research Foundation of Korea/ ; MRF2007656//Medical Research Future Fund/ ; },
mesh = {Humans ; *Protein Aggregation, Pathological/metabolism/drug therapy ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Metals/chemistry/metabolism ; Animals ; Protein Aggregates ; },
abstract = {Protein aggregation is a pathological process associated with several human diseases termed proteinopathies, including neurodegenerative and metabolic disorders such as Alzheimer's disease, Parkinson's disease, type II diabetes, amyotrophic lateral sclerosis, and Huntington's disease. In these conditions, specific proteins misfold and accumulate into insoluble aggregates, disrupting normal cellular function and contributing to disease progression. Many studies have investigated the molecular mechanisms that underlie the aggregation pathways, the structure of aggregates, such as oligomeric intermediates and fibrils, and their cellular toxicity. Studies have also investigated the effects of cofactors like metals, lipids, other amyloid proteins, and small molecules. Recent research has increasingly emphasized the critical roles of metal ions such as copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn) in amyloid aggregation and toxicity. Alterations in metal ion transport, binding, or redox activity have been linked to the onset and progression of several amyloid-associated diseases. These metal ions can interact directly with amyloidogenic proteins, influencing their structural conformation, aggregation kinetics, and propensity to form toxic oligomers. This review aims to advance our understanding of how the regulation of metal ions within cells and their dysfunction contribute to the accumulation of harmful proteins, which is a key factor in proteinopathies. By examining the interactions between metal ions and key amyloidogenic proteins─including amyloid-β (Aβ), α-synuclein, tau, superoxide dismutase 1 (SOD1), human islet amyloid polypeptide (hIAPP), and insulin─we highlight both common and unique pathways through which metal ions influence protein aggregation. Additionally, this review explores the impact of metal ions on protein clearance mechanisms, such as autophagy and the ubiquitin-proteasome system, as well as emerging theranostic strategies. These include metal chelation therapies, metal-based imaging agents, and multifunctional compounds designed to restore metal balance while preventing aggregation and toxicity. By integrating biochemical, cellular, and therapeutic insights, this review contributes to a deeper understanding of the metallobiology of proteinopathies and supports the development of novel diagnostic and treatment approaches targeting metal-protein interactions.},
}

Humans
*Protein Aggregation, Pathological/metabolism/drug therapy
*Neurodegenerative Diseases/metabolism/drug therapy
*Metals/chemistry/metabolism
Animals
Protein Aggregates

@article {pmid42917882,
year = {2026},
author = {Gross, S and Koch, P and Strasser, A},
title = {Synthesis and Pharmacological Characterization of Novel Tetrahydropyridine-Based Muscarinic M5 Receptor Antagonists to Investigate the Difference in the SARs of Muscarinic Receptor Subtypes Utilizing Induced Fit Docking Studies.},
journal = {Journal of medicinal chemistry},
volume = {69},
number = {19},
pages = {21789-21811},
doi = {10.1021/acs.jmedchem.6c00587},
pmid = {42917882},
issn = {1520-4804},
mesh = {Molecular Docking Simulation ; Structure-Activity Relationship ; Animals ; Humans ; *Receptor, Muscarinic M5/antagonists & inhibitors/metabolism ; *Pyridines/pharmacology/chemistry/chemical synthesis ; *Muscarinic Antagonists/pharmacology/chemical synthesis/chemistry ; CHO Cells ; Cricetulus ; Radioligand Assay ; },
abstract = {Many studies and experiments suggest the muscarinic M5 receptor (M5R) as a potential target for the clinical treatment of drug abuse, schizophrenia, or Alzheimer's disease. In the present study, a library containing 39 novel hM5R antagonists based on an arecaidine (tetrahydropyridine) core was synthesized, pharmacologically characterized in radioligand competition binding or mini-G protein assays and analyzed in molecular docking studies to elucidate their binding modes and in vitro characteristics. Compound 56m showed low single-digit nanomolar affinity on hM5R combined with a 17-fold selectivity over hM2R, while compound 81d displayed good affinity on hM5R with a 3- to 12-fold selectivity over the other subtypes. Induced fit docking studies suggest the conserved Y2.60 and hM5R-unique Q45.51 as the responsible amino acids regarding affinity and selectivity.},
}

Molecular Docking Simulation
Structure-Activity Relationship
Animals
Humans
*Receptor, Muscarinic M5/antagonists & inhibitors/metabolism
*Pyridines/pharmacology/chemistry/chemical synthesis
*Muscarinic Antagonists/pharmacology/chemical synthesis/chemistry
CHO Cells
Cricetulus
Radioligand Assay

@article {pmid42903279,
year = {2026},
author = {Addo, A and Li, B and Murikinati, S and Gardner, R and Zhao, LR},
title = {Transcriptomic analysis identifies candidate molecular mechanisms underlying SCF+G-CSF-reduced neuropathology in aged APP/PS1 mice.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1705436},
pmid = {42903279},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a neurodegenerative disease characterized by amyloid plaque deposition, tau hyperphosphorylation, neuroinflammation, and cognitive decline. Our previous studies demonstrated that combined treatment with stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) reduces AD pathology in APP/PS1 mice. The present study aimed to explore the molecular mechanisms underlying the effects of SCF+G-CSF using transcriptomic analysis.

METHODS: Aged APP/PS1 mice received daily subcutaneous injections of SCF+G-CSF or vehicle for 12 days. RNA was extracted from brain tissue on day 13 for gene-chip analysis. Age-matched wild-type (WT) mice served as controls. Data were analyzed using TAC, STRING v12.0, Reactome, and ShinyGO 0.77. A total of 45,037 genes were analyzed. Twenty-seven differentially expressed genes (DEGs) met a ≥ 2-fold threshold in SCF+G-CSF-treated versus vehicle-treated APP/PS1 mice, whereas 89 DEGs met this threshold in APP/PS1 versus WT mice.

RESULTS: SCF+G-CSF treatment upregulated immune-related genes, including S100a8, S100a9, Ngp, Lcn2, Ltf, and Camp, which are associated with immune regulation and amyloid-related processes. Pathway analysis identified downregulation of IL-2, IL-4, IL-7, and EGFR1 signaling and enrichment of IL-17 signaling, suggesting modulation of both innate and adaptive immune responses. SCF+G-CSF also downregulated several genes with known oncogenic functions, including Cbl, Akap9, Kcnq1ot1, and Snhg11, suggesting a potential molecular overlap between cancer- and AD-related pathways. In addition, pathway enrichment analysis identified NADPH oxidase activation through Rho GTPase signaling and greater than 400-fold enrichment of metal ion sequestration pathways following SCF+G-CSF treatment.

CONCLUSION: SCF+G-CSF treatment was associated with broad transcriptional changes involving immune regulation, metal ion homeostasis, and genes with known oncogenic functions. These findings provide new insights into the molecular pathways influenced by SCF+G-CSF in aged APP/PS1 mice and identify candidate mechanisms and therapeutic targets for future investigation.},
}

@article {pmid42903366,
year = {2026},
author = {Bashirzade, AA and Tikhonova, MA and Belichenko, VM and Fedoseeva, LA and Belyaev, MD and Renn, TY and Chang, HM and Kolosova, NG and Belyaev, ND and Amstislavskaya, TG},
title = {Epigenetic regulation of the transcriptional activity of genes mediating the neuroprotective activity of ceftriaxone in the brain in a rat model of sporadic Alzheimer disease: the involvement of histone deacetylase 1.},
journal = {Vavilovskii zhurnal genetiki i selektsii},
volume = {30},
number = {6},
pages = {899-907},
doi = {10.18699/vjgb-26-91},
pmid = {42903366},
issn = {2500-0462},
abstract = {Histone deacetylases (HDACs) are enzymes that provide transcriptional repression, while HDAC inhibitors are considered to be potential drugs in the treatment of Alzheimer disease (AD). Earlier we found that ceftriaxone (CEF), an antibiotic with neuroprotective activity, augmented mRNA levels of Ide and Mme, encoding enzymes involved in the catabolism of amyloid beta in the amygdala of OXYS rats, a model of sporadic AD. On the other hand, disturbances of neurotrophic factors (BDNF in particular) play an important role in AD pathogenesis. Moreover, HDACs of class I (HDAC1) are involved in the regulation of Bdnf transcriptional activity. The study was aimed to assess the effects of CEF on HDAC1 enrichment at Mme, Ide, and Bdnf gene promoters in the amygdala of OXYS rats and on Bdnf mRNA levels in the amygdala of OXYS and Wistar rats. Chromatin immunoprecipitation and qPCR were utilized for epigenetic analysis and assay of Bdnf mRNA levels, respectively. Neither significant HDAC1 enrichment, nor its alteration under CEF treatment at the Mme or Ide promoters were found, whereas CEF attenuated HDAC1 binding at Bdnf promoter IV. This is a novel mechanism of transcription regulation by CEF in the brain, which may be involved in its neuroprotective activity. In 5-month-old OXYS rats, it seems to play a minor role, as CEF did not change Bdnf transcript 5 (containing exons IV and IX) levels. We were first to demonstrate the transcript-specific regulation of Bdnf transcription by CEF. CEF significantly increased the levels of Bdnf transcript 6 (containing exons VII, VIII, and IX). The results of our study can be taken into account in AD treatment.},
}

@article {pmid42903416,
year = {2026},
author = {Park, JJ and Chung, SY and Kim, SM and Yoo, HD},
title = {Post-traumatic cognitive decline and neurodegenerative disease: a narrative review and proposed framework for etiologic assessment.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1844523},
pmid = {42903416},
issn = {1664-2295},
mesh = {Humans ; *Neurodegenerative Diseases/etiology/diagnosis/diagnostic imaging ; *Brain Injuries, Traumatic/complications ; *Cognitive Dysfunction/etiology/diagnosis/diagnostic imaging ; Biomarkers ; Neuroimaging ; },
abstract = {BACKGROUND: When a patient with a history of traumatic brain injury (TBI) develops progressive cognitive decline months to years after injury, clinicians must consider injury sequelae, an independent neurodegenerative disease, or both. Existing diagnostic frameworks each address a different aspect of this question, and none was constructed to apportion contribution between them. The distinction matters for management because AD-directed therapy should be considered only after biological Alzheimer's disease (AD) has been established, followed by separate assessment of treatment eligibility and safety.

OBJECTIVE: To synthesise evidence on cognitive change after TBI and the clinical, biomarker, and neuroimaging information available when delayed decline is evaluated, and to propose a structure for that evaluation.

METHODS: Structured narrative review. A documented de novo PubMed search was conducted on 27 July 2026, covering January 2015 to the search date, using two complementary strategies: one addressing cognitive, functional and neurodegenerative outcomes after TBI, and one addressing biomarker and neuroimaging evidence with longitudinal and prognostic terms. Diagnostic and research criteria, neuropathological and mechanistic references, comparator biomarker studies, and treatment trials were identified through targeted retrieval and reference checking. Exhaustive title and abstract screening, dual-reviewer study selection, formal risk-of-bias assessment, and quantitative synthesis were not undertaken.

RESULTS: Four patterns of cognitive change after TBI are proposed as unvalidated longitudinal clinical heuristics rather than validated diagnostic categories, and no prevalence is estimated for any of them. Delayed progressive deterioration following an initial plateau presents the greatest diagnostic difficulty. Blood biomarkers can support evaluation for coexisting biological AD, but neurofilament light and glial fibrillary acidic protein kinetics vary with injury severity and sampling window, and no validated biomarker profile identifies injury-driven neurodegeneration in an individual patient. Tau-related pathology, impaired protein clearance, and chronic neuroinflammatory activity are plausible contributors not shown to form a unified causal cascade.

CONCLUSION: Current evidence supports structured longitudinal reassessment and evaluation of competing explanations rather than etiological classification by biomarker pattern. A proposed assessment pathway, and a framework for stating what can and cannot be concluded in an individual patient, are offered as testable structures, including for medicolegal settings in which causal attribution is requested.},
}

Humans
*Neurodegenerative Diseases/etiology/diagnosis/diagnostic imaging
*Brain Injuries, Traumatic/complications
*Cognitive Dysfunction/etiology/diagnosis/diagnostic imaging
Biomarkers
Neuroimaging

@article {pmid42903448,
year = {2026},
author = {Song, J and He, A and Li, S and Wu, Q},
title = {TPPU, a soluble epoxide hydrolase inhibitor, mitigates Aβ-induced neurotoxicity via dual modulation of mitochondrial stabilization and JNK suppression.},
journal = {Biochemistry and biophysics reports},
volume = {48},
number = {},
pages = {102806},
pmid = {42903448},
issn = {2405-5808},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, primarily driven by β-amyloid (Aβ) aggregation and neuronal apoptosis. This study aims to investigate the neuroprotective effects of soluble epoxide hydrolase (sEH) inhibition against Aβ-induced cytotoxicity in PC-12 cells, focusing on cell viability, apoptosis, and the c-Jun N-terminal kinase (JNK) signaling pathway. Western blotting and fluorometric assays revealed elevated sEH expression and activity in Aβ1-42-treated PC-12 cells compared to untreated controls. Treatment with N-[1-(1-Oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl]urea (TPPU), a potent sEH inhibitor, significantly attenuated Aβ-induced apoptosis in PC-12 cells and enhanced cell viability. These findings were corroborated by CCK-8 assays and flow cytometry analyses. Furthermore, TPPU reversed Aβ-induced cleaved Caspase-3 dysregulation and restored mitochondrial membrane potential. Notably, exogenous administration of epoxyeicosatrienoic acids partially mimicked the protective effects of TPPU, primarily by preserving mitochondrial function. Western blot analysis confirmed that TPPU pretreatment suppressed the phosphorylation of JNK, thereby contributing to its anti-apoptotic effects. Collectively, these findings demonstrate that TPPU attenuates Aβ-induced neurotoxicity via dual mechanisms-restoring mitochondrial function and suppressing JNK activation-highlighting its potential as a therapeutic agent for AD.},
}

@article {pmid42904391,
year = {2026},
author = {Hassanzadeh Dostkoh, R and Dastyafteh, N and Iraji, A and Karimian, S and Mohammadi-Khanaposhtani, M and Safapoor, S and Noori, M and Tahmasebi, E and Saeedi, S and Larijani, B and Mahdavi, M and Javanshir, S},
title = {New hybrid molecules with 2,3,4,9-tetrahydro-1H-carbazol-1,3,4-oxadiazole-N-phenylacetamide framework as potent cholinesterase inhibitors.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/17568919.2026.2748649},
pmid = {42904391},
issn = {1756-8927},
abstract = {AIMS: In this study, new 2,3,4,9-tetrahydro-1H-carbazol-1,3,4-oxadiazole-N-phenylacetamide hybrids 8a-n as potential dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for the treatment of Alzheimer's disease (AD) were introduced.

METHODS: The target compounds were designed using a molecular hybridization strategy and synthesized via straightforward chemical reactions. They were evaluated in vitro for their inhibitory activity against AChE and BChE. The mechanism of inhibition was investigated through kinetic studies. Computational methods, including molecular docking and molecular dynamics simulations, were employed to analyze binding interactions and complex stability. Finally, the drug-likeness and oral bioavailability of the compounds were assessed.

RESULTS: All synthesized compounds showed significant inhibitory effects against BChE and moderate inhibition against AChE. Compound 8m was identified as the most potent dual inhibitor, being approximately 18-fold more potent against BChE than the standard drug donepezil. Kinetic studies on compound 8m revealed a competitive mode of inhibition against AChE and BChE. Computational analyses confirmed that compound 8m forms more stable interactions and a more stable, compact complex with BChE compared with donepezil, characterized by reduced structural fluctuations and more persistent hydrogen bonding.

CONCLUSIONS: Compound 8m is a potent, competitive inhibitor of both AChE and BChE with a favorable drug-like profile and oral bioavailability.},
}

@article {pmid42904474,
year = {2026},
author = {Lakshmi, SM and Singh, V and Vanangamudi, M and Taj, T and Shahin Dh, H and Nath, R and Dutta, G and Avvari, SK and Sridhar, SB and Panigrahy, UP and Noushida, N and Chaudhary, P},
title = {Modulating Microglial Activation Through GLP-1 Pathways: A New Frontier in Neuroinflammation Research.},
journal = {The European journal of neuroscience},
volume = {64},
number = {8},
pages = {e70718},
doi = {10.1111/ejn.70718},
pmid = {42904474},
issn = {1460-9568},
mesh = {*Microglia/metabolism/drug effects/immunology ; Animals ; Humans ; *Neuroinflammatory Diseases/metabolism/drug therapy/immunology ; *Glucagon-Like Peptide 1/metabolism ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Neurodegenerative Diseases/metabolism/drug therapy/immunology ; Glucagon-Like Peptide-1 Receptor/metabolism ; Signal Transduction ; },
abstract = {Microglia are the immune cells resident in the central nervous system (CNS) and are involved in CNS homeostasis and in responses to injury and disease. Microglia, upon activation, become pro-inflammatory (M1) or anti-inflammatory (M2), with M1 being neurotoxic and M2 participating in tissue repair. The activation of microglia in neuroinflammation and pain hypersensitivity is important in the neurodegenerative disorders such as Parkinson's (PD) and Alzheimer's disease (AD). Recent investigations have identified GLP-1 receptor agonists (GLP-1 RAs) as potent pharmacological agents that can regulate the activity of the microglia. GLP-1RA attaches to the GLP-1 receptor found on the microglia to cause a phenotypic shift to the anti-inflammatory M2 form, which, in turn, reduces neuroinflammation and increases neuronal protection. Experimental evidence shows that GLP-1 RAs are effective at reducing hypersensitivity to pain, improving cognitive performance, and attenuating inflammatory effects in preclinical models of AD, PD, and multiple sclerosis (MS). All these facts suggest that GLP-1 RAs are a significant treatment option in chronic pain and neurodegenerative disease management, as they can change microglial polarization and suppress neuroinflammation.},
}

*Microglia/metabolism/drug effects/immunology
Animals
Humans
*Neuroinflammatory Diseases/metabolism/drug therapy/immunology
*Glucagon-Like Peptide 1/metabolism
*Glucagon-Like Peptide-1 Receptor Agonists
*Neurodegenerative Diseases/metabolism/drug therapy/immunology
Glucagon-Like Peptide-1 Receptor/metabolism
Signal Transduction

@article {pmid42905162,
year = {2026},
author = {Stapf, CD and Uzelac, Z and Iterbeke, L and Guthknecht, A and Barba, L and Strube, D and Kölsch, A and Kleeberg, K and Kendzierski, T and Roos, A and Steinacker, P and Abu-Rumeileh, S and Claeys, KG and Weishaupt, J and Mensch, A and Otto, M},
title = {Serum p-tau181 and p-tau217 levels in adolescents and adults with 5q spinal muscular atrophy.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42905162},
issn = {1432-1459},
support = {Clinician Scientist Programme n. CS25/01//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; Clinician Scientist Programm No. CS22/06//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; Clinician Scientist Programm No. CS26/01//Medical Faculty of Martin-Luther-University Halle-Wittenberg/ ; FTLDc 01GI1007A//German Federal Ministry of Education and Research/ ; D.3830//foundation of the state Baden-Württemberg/ ; },
mesh = {Humans ; Female ; *tau Proteins/blood ; Male ; Adolescent ; Biomarkers/blood ; Retrospective Studies ; Adult ; *Muscular Atrophy, Spinal/blood/drug therapy/physiopathology ; Middle Aged ; Phosphorylation ; Young Adult ; Amyotrophic Lateral Sclerosis/blood ; Alzheimer Disease/blood ; *Spinal Muscular Atrophies of Childhood/blood ; Aged ; Longitudinal Studies ; },
abstract = {BACKGROUND: Reliable blood biomarkers for longitudinal monitoring in adolescent and adult 5q spinal muscular atrophy (SMA) are lacking. Phosphorylated tau (p-tau) species are elevated in serum in amyotrophic lateral sclerosis (ALS), where they may reflect peripheral nerve and muscle pathology. We aimed to investigate serum p-tau181 and p-tau217 as longitudinal biomarkers in adolescent and adult SMA and assessed associations with clinical parameters.

METHODS: In this retrospective multi-centre study, we assessed serum p-tau181 and p-tau217 levels in adults with 5q SMA under treatment with nusinersen or risdiplam, comparing levels with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and non-neurodegenerative disease controls. Associations with motor function, respiratory capacity, creatine kinase (CK), and neurofilament light chain (NfL) were assessed using linear mixed-effects models adjusted for age and sex.

RESULTS: Serum p-tau181 was higher in SMA than in disease controls (β = -0.48, 95%-CI -0.81 to -0.15), but lower than in ALS (β = 0.99, 95%-CI 0.58 to 1.39) and AD (β = 0.56, 95%-CI 0.11 to 1.00). P-tau181 declined from baseline to FUP2 (Δ median -1.80 pg/mL, IQR -5.90 to 2.10); p-tau217 showed no longitudinal change. P-tau181 and p-tau217 were positively associated with motor function, functional status, respiratory capacity, and CK, with no association with NfL. In exploratory analyses, higher baseline p-tau181 was associated with greater HFMSE decline (β = 1.79, 95%-CI 0.59 to 2.99).

CONCLUSIONS: Serum p-tau181 and p-tau217 appear to reflect ongoing muscle turnover in adult SMA, declining as muscle mass decreases. Higher baseline p-tau181 was associated with subsequent functional deterioration, suggesting potential utility as a biomarker of active denervation and disease monitoring.},
}

Humans
Female
*tau Proteins/blood
Male
Adolescent
Biomarkers/blood
Retrospective Studies
Adult
*Muscular Atrophy, Spinal/blood/drug therapy/physiopathology
Middle Aged
Phosphorylation
Young Adult
Amyotrophic Lateral Sclerosis/blood
Alzheimer Disease/blood
*Spinal Muscular Atrophies of Childhood/blood
Aged
Longitudinal Studies

@article {pmid42905229,
year = {2026},
author = {Halmos, PM and Dobi, B and Vinnai, P and Ajtay, A and Bereczki, D and Kovács, T},
title = {Memantine in the treatment of dementia: a nationwide real-world analysis.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42905229},
issn = {2509-2723},
support = {FIKP IGSZF/123338-2/2021-ITMFIKP IGSZF/123338-2/2021-ITM//Nemzeti Kutatási, Fejlesztési és Innovaciós Alap/ ; },
abstract = {Despite the growing global burden of dementia, real-world data that adequately reflect the current state of healthcare systems, dementia care pathways, and the actual impact of pharmacological treatment practices remain limited, hindering the evidence-based planning and implementation of novel therapies. This retrospective cohort study evaluated nationwide anti-dementia drug treatment practices, particularly focusing on memantine use, and their effect on survival. Using the nationwide NEUROHUN database, data from 398,584 patients with dementia from 2010 to 2020 in Hungary were analyzed (mean age at diagnosis 75.22 years). Kaplan-Meier analyses and multivariable Cox proportional hazards models were conducted to evaluate survival outcomes, adjusting for age and sex. Annual prescription prevalence, medication adherence, and persistence metrics were also calculated. Only 13% of patients received any anti-dementia drug (donepezil, rivastigmine, or memantine); among those treated, 24% received memantine as monotherapy. Untreated patients had the shortest median survival (3.1 years), followed closely by those on memantine monotherapy alone (3.7 years). This pattern likely reflects the older age, delayed diagnosis, and presumably more advanced disease stage of these patients rather than a direct effect of memantine. Patients receiving memantine and donepezil showed the lowest mortality risk (HR = 0.581) compared to the untreated group. Symptomatic pharmacological treatments are likely to remain important adjuncts to emerging disease-modifying therapies, given their evidence-based benefits in dementia care. This is the first study in the Central-Eastern European region to evaluate memantine under real-world conditions, highlighting the high proportion of late diagnoses and underscoring the need to establish earlier and more efficient diagnostic pathways.},
}

@article {pmid42905846,
year = {2026},
author = {Shee, S and Huang, M and Baghel, MS and Zheng, Y and Lun, S and Yadav, SK and Yadav, NN and Ruiz-Gonzalez, CE and Tyagi, S and Nuermberger, E and Jain, SK and Bhujwalla, ZM and Slusher, BS and Wong, PC and Bishai, W},
title = {BCG vaccination mitigates tau pathology and restores cognitive function in PS19 mice.},
journal = {Science advances},
volume = {12},
number = {43},
pages = {eaej4603},
pmid = {42905846},
issn = {2375-2548},
mesh = {Animals ; Mice ; *tau Proteins/metabolism ; *BCG Vaccine/pharmacology/immunology/administration & dosage ; *Tauopathies/prevention & control/pathology/metabolism ; Disease Models, Animal ; *Cognition/drug effects ; Vaccination ; Microglia/metabolism ; Hippocampus/metabolism/pathology ; Mice, Transgenic ; Magnetic Resonance Imaging ; },
abstract = {Retrospective studies in patients with nonmuscle invasive bladder cancer have reported a significant reduction in Alzheimer's disease incidence (12 to 78%) among Bacille Calmette-Guérin (BCG) recipients versus controls. To investigate the underlying mechanisms, we evaluated BCG in the PS19 mouse model of tauopathy. We found that BCG administration reduced hippocampal phospho-tau and microgliosis while preserving neuronal markers. In vivo volumetric T2-magnetic resonance Imaging (MRI) demonstrated attenuation of brain atrophy accompanied by increased glutamate-weighted chemical exchange saturation transfer-MRI signals. Functionally, BCG-treated mice showed improved performance in the novel object recognition test, as well as improved body-weight maintenance and survival. Transcriptomic profiling of the hippocampus revealed near complete normalization of the PS19 disease-associated gene expression signature toward that of healthy controls. Flow cytometric profiling of brain myeloid populations demonstrated a reduction in activated resident microglia, but total microglia cells remain elevated. Moreover, an increase of trained immunity marker CD80 on the recruited peripheral myeloid cells ensues following BCG treatment. Consistent with this shift in myeloid state, primary brain myeloid cells from BCG-treated mice also exhibited enhanced phagocytosis of fluorescein isothiocyanate-labeled tau fibrils and increased lactate production. Together, these findings indicate that BCG induces systemic and central nervous system myeloid cell reprogramming that limits neuroinflammation, enhances tau clearance, and rescues cognitive and neurodegenerative phenotypes in a tauopathy model. BCG is a safe, readily available therapy that merits consideration as a preventive agent against dementia.},
}

Animals
Mice
*tau Proteins/metabolism
*BCG Vaccine/pharmacology/immunology/administration & dosage
*Tauopathies/prevention & control/pathology/metabolism
Disease Models, Animal
*Cognition/drug effects
Vaccination
Microglia/metabolism
Hippocampus/metabolism/pathology
Mice, Transgenic
Magnetic Resonance Imaging

@article {pmid42906297,
year = {2026},
author = {Gu, M and Li, J and Liu, B and Yang, N and Lang, M and Han, Y and Kou, B and Yang, P and Ding, W and Lin, W and Zhu, S and Tong, Q and Quan, L},
title = {A synergistic platform integrating iodinated BODIPY photosensitizers and microglial cells for superior photodynamic antibacterial efficacy.},
journal = {Bioorganic chemistry},
volume = {184},
number = {},
pages = {110663},
doi = {10.1016/j.bioorg.2026.110663},
pmid = {42906297},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is closely linked to gut dysbiosis and microbial translocation, highlighting an urgent need for antimicrobial strategies that combine high efficiency with host immune compatibility. Photodynamic therapy using photosensitizers offers a promising approach, yet conventional agents often lack the ability to engage host defense mechanisms for sustained bacterial clearance. Here, we report a synergistic platform that integrates iodinated BODIPY-based photosensitizers with BV-2 microglial cells to achieve enhanced antibacterial efficacy through the cooperative action of photodynamic killing and microglial phagocytosis. A series of BODIPY derivatives bearing iodine atoms at the 2,6-positions and functionalized with isocyano or aldehyde groups at the meso-position were synthesized. Among them, NC-PhBDP-I exhibits both stable and rapid reactive oxygen species (ROS) generation capacity and negligible cytotoxicity, positioning it as an ideal candidate for synergistic application. Mechanistically, photodynamic treatment with NC-PhBDP-I not only induces rapid bacterial membrane disruption but also potently activates BV-2 microglial phagocytic activity, leading to accelerated clearance of residual bacteria that survive the initial photodynamic insult. This dual-modal action results in a pronounced synergistic effect, with the combination markedly surpassing the sum of individual effects from photodynamic treatment or microglial engagement alone. Our findings establish an integrated chemical-biological platform that leverages both photodynamic and innate immune functions, offering a promising strategy for combating bacterial infections in the context of AD and beyond.},
}

@article {pmid42906579,
year = {2026},
author = {Yuwadee, A and Boonprasert, K and Na-Bangchang, K},
title = {Pharmacological Activities of Centella asiatica: A Systematic Review of Preclinical and Clinical Evidence on Cardiovascular, Neurological, Antioxidant, and Anti-inflammatory Effects.},
journal = {Planta medica},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2969-6239},
pmid = {42906579},
issn = {1439-0221},
support = {N42A671041//National Research Council of Thailand (NRCT)/ ; 2025,TUFT-FF49/2569//Thailand Science Research and Innovation Fundamental Fund Fiscal Year/ ; },
abstract = {Centella asiatica (L.) (Gotu Kola) is a medicinal herb traditionally used in Asia for cognitive enhancement, wound healing, and systemic disorders. This systematic review appraises preclinical and clinical evidence on its cardiovascular and neurological effects. Following PRISMA 2020, we searched PubMed, ScienceDirect, Scopus, Embase, and ClinicalTrials.gov (to June 2026) for studies of whole-plant extracts or bioactive compounds (asiatic acid, asiaticoside, madecassoside, madecassic acid, caffeoylquinic acids) in vitro, in animals, or in humans, excluding dermatological studies, reviews, and articles lacking methods. Sixty-two studies met criteria: 54 preclinical and eight clinical trials, assessed using SYRCLE, an in vitro checklist, and Cochrane RoB 2. Preclinically, C. asiatica modulated ischemia-reperfusion injury, reduced doxorubicin-induced cardiotoxicity, improved cognitive deficits in Alzheimer's and Parkinson's models, and showed antidepressant-like effects, via Nrf2/HO-1 antioxidant activation and NF-κB/MAPK anti-inflammatory suppression. Clinical evidence was mixed: Gotu Kola matched or exceeded folic acid for poststroke vascular cognitive impairment, and three trials of a standardized triterpenic fraction (TTFCA) improved microcirculation in venous hypertensive and diabetic microangiopathy; however, a type 2 diabetes trial found no significant effect on glycated hemoglobin, glucose, or LDL cholesterol, a mild cognitive impairment trial found no added benefit over exercise alone, and a Phase 1 safety trial is ongoing. C. asiatica shows preclinical promise as a multitarget cardiovascular and neurological agent, but clinical evidence remains limited and inconsistent, compounded by an 800-fold preclinical dosing range, variable treatment durations, and geographic concentration (47% from one country). Larger, standardized, multiregion trials targeting these outcomes are needed before therapeutic claims are warranted.},
}

@article {pmid42906637,
year = {2026},
author = {Hong, EH and Kim, A and Kim, KY and Rhee, HY and Shin, DI and Kim, JY and Cho, SJ and Kim, DY and Jahng, GH and Lee, HB and Park, WY and Kim, BH and Chung, WK},
title = {Cognitive outcomes of low-dose whole-brain radiation therapy in mild Alzheimer's disease: A multicenter, randomized, sham-controlled phase II clinical trial.},
journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology},
volume = {},
number = {},
pages = {111833},
doi = {10.1016/j.radonc.2026.111833},
pmid = {42906637},
issn = {1879-0887},
abstract = {BACKGROUND AND PURPOSE: Low-dose radiotherapy (LDRT) has shown potential in preclinical Alzheimer's disease (AD) models, but controlled clinical evidence is limited. We evaluated two whole-brain LDRT regimens in mild AD.

MATERIALS AND METHODS: In this multicenter, participant-blinded, three-arm phase II trial, amyloid-positive participants were randomized 1:1:1 to sham irradiation, 0.04 Gy per fraction (0.24 Gy total), or 0.5 Gy per fraction (3 Gy total), delivered twice weekly for 3 weeks. The primary endpoint was change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) score from baseline to 6 months. Twelve-month analyses were exploratory. Longitudinal outcomes were estimated using mixed-effects models.

RESULTS: Forty-one participants were randomized; 36 were included in the modified intention-to-treat population and 30 completed 12-month follow-up. At 6 months, adjusted between-group differences in ADAS-cog change versus sham were -2.08 points (95% CI, -7.06 to 2.89; p = 0.401) for 0.24 Gy and -2.92 points (95% CI, -6.72 to 0.89; p = 0.129) for 3 Gy. At 12 months, the corresponding exploratory differences were -3.02 points (95% CI, -10.00 to 3.96; p = 0.386) and -5.36 points (95% CI, -10.58 to -0.14; nominal p = 0.044). No treatment-related adverse events or radiologic safety concerns were identified.

CONCLUSIONS: The prespecified 6-month primary endpoint was not met. Exploratory 12-month and secondary analyses showed differences in selected cognitive outcomes, although the findings varied across doses and outcomes. These findings did not establish efficacy or a dose-response relationship and warrant confirmation in a larger trial with longer follow-up.},
}

@article {pmid42906650,
year = {2026},
author = {Zhai, Y and Acuña, MA and Krzyszkowski, A and Al-Haj, S and Nevian, NE and Finn, DP and Nevian, T and Kwakowsky, A},
title = {Caffeine attenuates Aβ-induced hippocampal dysfunction alongside changes in adenosine receptor-linked GABA handling and neuronal excitability.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {109697},
doi = {10.1016/j.phrs.2026.109697},
pmid = {42906650},
issn = {1096-1186},
abstract = {Synaptic and circuit dysfunction in the hippocampus is an early feature of Alzheimer's disease, involving disturbances at both excitatory and inhibitory synapses. Adenosine receptors (ARs) regulate hippocampal glutamatergic and GABAergic signaling. Caffeine, a non-selective AR antagonist, has well-established neuroprotective actions. We examined whether caffeine attenuates amyloid-β (Aβ)-induced changes in neuronal viability, GABA handling, intrinsic excitability and synaptic excitation/inhibition (E/I) balance, and whether these functional effects occur alongside changes in AR and GABA transporter 1 (GAT-1) protein abundance. Primary mouse hippocampal cultures were exposed to Aβ1-42 (1nM) and/or caffeine (0.1, 1, 25, and 50µM) for culture-based assays, whereas acute hippocampal slices were exposed to Aβ1-42 (100nM) and/or caffeine (25µM) during whole-cell patch-clamp recordings from CA1 pyramidal neurons. In cultures, Aβ increased neuronal death, confirming previous reports, and caffeine co-treatment attenuated this effect. Total GAT-1, A1R and A2AR protein levels were unchanged, whereas Aβ reduced neuronal A1R immunoreactivity; this reduction was not observed with caffeine co-treatment. Radiometric assays identified treatment-associated differences in 1-h [3]H-GABA accumulation and basal [3]H-GABA outflow, including a non-significant trend toward increased accumulation after Aβ exposure and reduced accumulation in the Aβ+caffeine condition. In slices, Aβ flattened the frequency-current relationship and transiently reduced the E/I ratio, whereas these changes were not observed during caffeine co-application; subsequent caffeine exposure restored firing output after 30min of Aβ exposure. Further experiments are required to establish if changes in A1R immunoreactivity or radiometric GABA handling contribute to the electrophysiological effects.},
}

@article {pmid42906859,
year = {2026},
author = {Haller, OJ and Carr, LM and Semendric, I and George, RP and Whittaker, AL and Collins-Praino, LE},
title = {Evaluating the NLRP3 inflammasome in chemotherapy-induced cognitive impairment: A multi-timepoint study of methotrexate and 5-fluorouracil in female rats.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116542},
doi = {10.1016/j.bbr.2026.116542},
pmid = {42906859},
issn = {1872-7549},
abstract = {Chemotherapy-induced cognitive impairment (CICI) affects many cancer survivors, who often report cognitive difficulties during and/or after treatment that reduce quality of life. While the exact mechanisms that underlie CICI are unclear, neuroinflammation is widely proposed to contribute. One candidate mediator is the nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor protein 3 (NLRP3) inflammasome, which drives microglial inflammation and is implicated in Parkinson's and Alzheimer's disease. This study therefore investigated whether NLRP3 inflammasome components are altered in a rat model of CICI. Female Sprague Dawley rats were randomly allocated to receive methotrexate (MTX), 5-fluorouracil (5-FU) or saline (n = 18/treatment) and were euthanised at 96-hours, 31-days or 93-days post-treatment (n = 6/treatment/timepoint). This cohort was previously shown to develop cognitive deficits. In the prefrontal cortex and hippocampus, NLRP3 and pro-caspase-1 were measured by western blot, and interleukin-1β (IL-1β) by ELISA. Microglial number and activation were assessed by ionized calcium-binding adaptor molecule 1 (IBA1) immunohistochemistry (n = 4/treatment/timepoint). Compared with saline controls, neither chemotherapy altered NLRP3 or pro-caspase-1 in either brain region at any timepoint, and treatment effect sizes were small (ηp[2] ≤ 0.06). IL-1β, detectable only at 96-hours, was also unchanged. Similarly, there were no differences in either total microglial number or the percentage of activated microglia. These findings provide no evidence that NLRP3 inflammasome components are altered in this female rat model of CICI at the timepoints examined. However, as inflammasome assembly and activation were not directly assessed, future work should measure ASC speck formation, cleaved caspase-1 and mature IL-1β, and include earlier timepoints, particularly within the first two weeks after chemotherapy.},
}

@article {pmid42907679,
year = {2026},
author = {Wu, Y and Zhu, L and Chen, J and Liu, J and Yin, K and Yang, X},
title = {Real-world safety and efficacy of lecanemab in the treatment of Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42907679},
issn = {1432-1459},
support = {82560237，81960242//National Natural Science Foundation of China/ ; 202301AS070045//Applied Basic Research Foundation of Yunnan Province/ ; 202102AA310061//Yunnan Province Clinical Research Center for Neurological Disease/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy ; },
abstract = {BACKGROUND: Despite the approval of lecanemab for Alzheimer's disease (AD), evidence regarding its performance outside controlled trial settings remains scarce, leaving its real-world safety and clinical utility largely unknown.

METHODS: We searched PubMed, Embase, and Web of Science (through October 1, 2026) for real-world studies of lecanemab in AD. Outcomes included ARIA, discontinuation, infusion-related reactions, serious adverse events, MMSE, MoCA, CDR-SB, and amyloid PET. Random-effects models with REML and Hartung-Knapp adjustment were used. Subgroup analyses were stratified by region, APOE ε4 genotype, baseline CDR score, microhemorrhage, and white matter hyperintensity. Sensitivity analyses included leave-one-out and Egger's test. Scenario-based sensitivity analyses were also performed for overlapping cohorts. This study was registered with PROSPERO (No. CRD420261333493).

RESULTS: Thirty-seven studies were included. For overlapping cohorts, the largest dataset per outcome was retained after prioritizing peer-reviewed reports. Pooled incidence of any ARIA was 15.1% (US vs Asian studies 19.5% vs 9.7%), ARIA-E 6.5% (10.6% vs 2.5%), ARIA-H 11.5% (15.2% vs 7.0%), and symptomatic ARIA 1.3% (3.3% vs 0.1%). APOE ε4 homozygotes showed the highest rates across all three subtypes (any ARIA 34.1%, ARIA-E 10.3%, ARIA-H 18.9%), followed by heterozygotes (14.5%, 4.7%, 12.0%) and non-carriers (11.0%, 2.9%, 6.7%). Baseline microhemorrhage was associated with higher any ARIA (23.4% vs 11.5%) and ARIA-H (19.3% vs 4.2%), but not ARIA-E (5.4% vs 5.7%). ARIA incidence did not differ significantly by baseline CDR severity or deep white matter hyperintensity burden. Except for MoCA at ≤ 3 months (MD 0.515, 95% CI 0.451-0.578; 2 studies), no statistically significant changes were observed in cognitive outcomes. Amyloid PET decreased at 6 months (Centiloid MD -28.453, 95% CI -37.708 to -19.198) and 12 months (SUVR MD -0.171, 95% CI -0.291 to -0.052). Discontinuation rates were 3.5% (ARIA-related), 6.2% (adverse event-related), and 12.2% (total); infusion-related reactions were 18.5% and serious adverse events 2.8%. Sensitivity analyses supported robustness.

CONCLUSIONS: This is the first large-scale systematic review and meta-analysis of real-world studies of lecanemab reporting safety and efficacy outcomes. Safety outcomes particularly ARIA may be influenced by APOE ε4 genotype and baseline microbleeds. Cognitive outcomes lacking control data cannot confirm efficacy and longer-term cross-regional controlled studies are needed.},
}

Humans
*Alzheimer Disease/drug therapy

@article {pmid42908770,
year = {2026},
author = {Yoon, S and Ahn, J and Kim, S and Kim, K and Kim, SY and An, SK and Na, DG and Kim, YJ and Kwak, K and Seo, SW and Na, DL},
title = {Topography and risk factors of amyloid-related imaging abnormality: real-world data from 168 aducanumab-treated patients at a private clinic in South Korea.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70473},
pmid = {42908770},
issn = {2352-8729},
abstract = {INTRODUCTION: Amyloid-related imaging abnormalities (ARIA) are a major safety concern in anti-amyloid therapy for Alzheimer's disease (AD), but real-world data remain limited. We investigated risk factors, temporal characteristics, and spatial distribution of ARIA in aducanumab-treated patients and assessed the safety of apolipoprotein E (APOE) genotype-tailored dosing.

METHODS: We retrospectively analyzed 168 patients with a Clinical Dementia Rating (CDR) of 0.5 to 2 treated with aducanumab between 2022 and 2024. Dosing was individualized by APOE genotype. Serial magnetic resonance imaging (MRI) detected ARIA, multivariable regression identified risk factors, and ARIA with edema or effusion (ARIA-E) lesions were manually segmented to generate topographical maps.

RESULTS: Among 164 patients, 33 (20.1%) developed ARIA-E, with incidence increasing by APOE ε4 status (12.5% non-carriers, 19.5% heterozygotes, 50.0% homozygotes; p = 0.002). Lesions showed posterior predominance. Independent risk factors included APOE ε4 homozygosity, CDR 2, and hypertension. Most cases did not require treatment discontinuation.

DISCUSSION: ARIA-E risk during aducanumab therapy was influenced by genetic and clinical factors, supporting genotype-tailored titration in practice.},
}

@article {pmid42909413,
year = {2026},
author = {Jie, S and Lei, Z},
title = {Pyroptosis: a potential target and research progress of exercise in ameliorating Alzheimer's disease pathology.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1983962},
pmid = {42909413},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD), a debilitating neurodegenerative disorder that severely threatens elderly health, is clinically manifested as cognitive decline and driven by core pathological hallmarks including amyloid-beta (Aβ) deposition, tau hyperphosphorylation, and chronic neuroinflammation. Recent studies have indicated that its pathophysiological process is closely associated with pyroptosis, and excessive activation of pyroptosis drives a vicious cycle of amplified inflammation and neuronal injury. Although accumulating evidence suggests that exercise serves as an effective non-pharmacological intervention to suppress pyroptosis and alleviate AD, the intrinsic interactive mechanisms among exercise, pyroptosis and the pathological progression of AD remain incompletely elucidated. Therefore, this review systematically summarizes the functional mechanisms of pyroptosis in the pathological progression of AD and discusses the potential neuroprotective effects of exercise intervention. It further focuses on analyzing the specific mechanisms by which exercise inhibits pyroptosis via regulating the NLRP3 inflammasome pathway, aiming to identify novel targets for the prevention and treatment of AD and provide a theoretical basis for formulating scientific exercise intervention strategies.},
}

@article {pmid42909680,
year = {2026},
author = {Sura, S and Jagadeesan, S and Masrudin, SS and Moklas, MAM and Nor, NHM},
title = {Cannabidiol in Alzheimer's disease: evidence-weighted molecular mechanisms and translational challenges.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42909680},
issn = {1573-4978},
support = {(Grant No. GP-IPM/2021/9700000)//Universiti Putra Malaysia through the Institutional Grant Scheme/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Cannabidiol/therapeutic use/pharmacology/metabolism ; Animals ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; Signal Transduction/drug effects ; },
abstract = {Alzheimer's disease (AD) is a complex, progressive neurodegenerative disorder in which amyloid-β accumulation, tau dysregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction, synaptic loss and neurodegeneration interact to drive memory loss and cognitive decline. Despite advances in symptomatic therapies and anti-amyloid agents, clinical benefit remains modest, supporting interest in polypharmacological approaches. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid that interacts with several signalling systems relevant to AD, including cannabinoid-related pathways, peroxisome proliferator-activated receptor-γ (PPARγ), transient receptor potential vanilloid 1 (TRPV1) channels, 5-HT1A signalling, fatty acid-binding proteins involved in anandamide transport, GPR55 and adenosine transporters. The most consistent preclinical findings indicate that CBD attenuates neuroinflammatory and oxidative responses and improves selected behavioural outcomes. Evidence for amyloid-related effects is supportive but heterogeneous. Direct evidence for tau modulation has expanded in transgenic and chemically induced models, but findings remain model-dependent, whereas mitochondrial rescue and adult hippocampal neurogenesis are less firmly established. Methodological variability in CBD source, formulation, dose, route, treatment window, sex, age and outcome selection limits direct comparison between studies. Work on other cannabinoids and CBD:Δ9-THC combinations is discussed for context, and current evidence does not establish CBD as a disease-modifying treatment in AD. Overall, current preclinical evidence supports continued investigation of CBD as a multi-target neuroprotective candidate in AD, provided that future studies use standardized, mechanism-focused and translationally relevant designs. This review compares preclinical evidence across pathological domains and identifies translational research priorities.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Cannabidiol/therapeutic use/pharmacology/metabolism
Animals
Oxidative Stress/drug effects
Amyloid beta-Peptides/metabolism
Signal Transduction/drug effects

@article {pmid42909797,
year = {2026},
author = {Cicin, FN},
title = {The Role of Digital Twins in Clinical Trials: A New Perspective on Methodological and Statistical Challenges.},
journal = {Therapeutic innovation & regulatory science},
volume = {},
number = {},
pages = {},
pmid = {42909797},
issn = {2168-4804},
abstract = {BACKGROUND: Randomized controlled trials (RCTs) remain the gold standard for evaluating medical interventions, yet they face persistent methodological challenges: patient dropout, inadequate sample sizes, premature termination, missing data, and the limitations of indirect treatment comparisons. The emergence of digital twin technology-computational patient representations that generate simulated clinical trajectories statistically indistinguishable from real-world data-offers a promising methodological complement to address these limitations.

APPROACH: We synthesize evidence from key methodological literature, regulatory guidance (ICH E9(R1), FDA, EMA), and proof-of-concept studies across oncology, neurology, and Alzheimer's disease. A taxonomy of in silico clinical trial approaches provides the organizational framework. This article is a narrative perspective rather than a systematic review; no predefined search strategy, database range, or inclusion/exclusion criteria were applied.

RESULTS: Digital twins may provide complementary methodological approaches across nine trial challenges: model-based sensitivity analyses for missing (MNAR) outcomes; Bayesian and posterior predictive modeling of partially observed longitudinal outcomes; prognostic covariate adjustment and virtual augmentation to improve efficiency; prospective simulation of futility stopping rules; prospective calibration of efficacy stopping boundaries; individualized control-arm (ICA) construction; hybrid augmented and synthetic control strategies; pre-trial protocol optimization through in silico simulation; and population-adjusted indirect treatment comparison.

CONCLUSIONS: Digital twins represent an emerging methodological ecosystem rather than isolated tools. Their methodological potential depends on consistent validation and explainability standards; frameworks for detecting algorithmic bias; clarification of regulatory acceptance criteria; and comprehensive data infrastructure addressing representativeness gaps. Digital twin approaches should be viewed as complementary to-not replacements for-established randomized trial methodology.},
}

@article {pmid42909824,
year = {2026},
author = {Liu, X and Du, X and Qi, S and Yuan, L and Liu, L and Zhang, K and Wang, L and Zhang, W and Liu, Q and Wu, M and Huang, Y},
title = {Circadian rhythms in health and disease.},
journal = {Molecular biomedicine},
volume = {7},
number = {1},
pages = {},
pmid = {42909824},
issn = {2662-8651},
support = {82201594//National Natural Science Foundation of China/ ; 81502582//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Circadian Rhythm/physiology/genetics ; Animals ; },
abstract = {Circadian rhythms, serving as a crucial temporal bridge linking neural activity and pathological biology, are regulated by central pacemaker neurons to maintain cellular homeostasis and coordinate diverse biological processes. Circadian rhythm disruption is closely associated with various diseases, including neurodegenerative disorders, metabolic disorders, and cancer. Circadian rhythms are controlled by core clock genes, such as BMAL1 and CLOCK, modulating numerous physiological processes, encompassing metabolism, immune responses, neural activity, and hormone regulation. Circadian rhythms disruptions arising from shift work, jet lag, or inconsistent sleep schedules are implicated in both the onset and progression of numerous diseases, notably Alzheimer's disease, Parkinson's disease, diabetes, and cardiovascular disease. The article highlights how circadian dysregulation alters cellular processes to potentially accelerate disease progression. Circadian disruption results in impaired immune function, further promoting disease development and resistance to treatment. Potential therapeutic applications based on circadian biology, such as chronotherapy and personalized medicine, are also discussed. Recent technological advances, embodied in wearable devices and omics approaches, are increasingly providing deeper insights into circadian biology. Further unveiling the role of circadian in health and disease opens new avenues for tailoring treatment timing to patients' biological rhythms, thereby enhancing therapeutic outcomes across various diseases. By bridging fundamental circadian mechanisms with clinical pathology, this review provides a roadmap for future chronotherapeutic interventions in precision medicine.},
}

Humans
*Circadian Rhythm/physiology/genetics
Animals

@article {pmid42911093,
year = {2026},
author = {Smith, PJ and Ingle, KK and Nakamura, Z and Strauman, T and Keyserling, T and Parker, D and Nelson, C and Muoio, DM and Huffman, KM},
title = {Time restricted eating through self-regulatory behaviors for metabolic and cognitive health in mild cognitive impairment: Feasibility and acceptability findings from the TEMPO trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497622},
doi = {10.1177/13872877261497622},
pmid = {42911093},
issn = {1875-8908},
abstract = {BackgroundMild cognitive impairment (MCI) and Alzheimer's disease and related dementias (ADRD) occur at 1.5-2-fold higher rates among adults with obesity or metabolic syndrome. Time restricted eating (TRE) represents a portable and potentially effective strategy to enhance metabolic function and reduce ADRD risk.ObjectiveTo assess the feasibility and acceptability of TRE among older adults with MCI and metabolic risk.MethodsWe assessed a 16-18-h TRE protocol, implemented 2-3 days per week, among older adults (65-85 years of age) with MCI (proposed n = 40) and metabolic risk over 12-weeks. Feasibility was assessed by recruitment and completion of trial activities, while Acceptability was assessed using psychometric self-report. Cognitive function was assessed using a standard neuropsychological test battery, including tests of Executive Function/Processing Speed (Trail Making, Stroop, Controlled Oral Word Association Test, Animal Naming, Digit Span, and Digit Symbol Substitution Tests), Learning/Memory (Hopkins Verbal Learning Test-Revised and Benton Visual Memory Test-Revised. We also examined treatment- and state-dependent changes in metabolic and inflammatory biomarkers, including multiple ketone metabolites and pro-inflammatory cytokines, among others.ResultsFrom 9/28/23 until 3/25/25, thirty-three individuals (83% of target goal [n = 40]) were recruited. Enrolled participants completed all treatment sessions and assessments (100%) and self-reported Acceptability was high. Modification of study recruitment practices and inclusion criteria allowed for an increased screening-to-recruitment ratios over the course of the trial, rising from 1.3% to 11.1%, while still resulting in appropriate recruitment of individuals with MCI.ConclusionsTRE is a feasible and acceptable intervention among older adults with metabolic risk factors.},
}

@article {pmid42911292,
year = {2026},
author = {Ng, S and Somvanshi, RK and Kumar, U},
title = {Cannabidiol Regulates Amyloid-β Plaque Deposition and Astrogliosis in the 5xFAD Transgenic Mouse Model.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {42911292},
issn = {1559-1166},
mesh = {Animals ; *Cannabidiol/pharmacology/therapeutic use ; Mice, Transgenic ; *Plaque, Amyloid/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; PPAR gamma/metabolism/genetics ; Mice ; Receptor, Cannabinoid, CB1/metabolism/genetics ; Receptor, Cannabinoid, CB2/metabolism/genetics ; Astrocytes/drug effects/metabolism ; Glial Fibrillary Acidic Protein/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; *Gliosis/drug therapy ; Cerebral Cortex/metabolism/drug effects ; Hippocampus/metabolism/drug effects ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {Alzheimer's Disease (AD) is marked by the accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles, and neuroinflammation. Cannabidiol (CBD), the major non-psychoactive compound of Cannabis, has demonstrated significant pharmacological potential for the treatment of AD. CBD is known to act on various receptors, including cannabinoid receptor 1 (CB1R) and 2 (CB2R), and peroxisome proliferator activated receptor γ (PPARγ). However, the precise changes in receptor expression in AD, as well as following CBD treatment, remain unclear and inconsistent in literature. To address this, we performed immunohistochemistry and immunoblotting in AD-compromised brain regions, specifically the cortex and the hippocampus. In 5xFAD transgenic (TG) mice, we noted strong deposition of Aβ plaques and glial fibrillary acidic protein (GFAP)- positive astrocytes. However, following CBD treatment, Aβ plaque burden and GFAP accumulation were significantly reduced. We observed increased CB1R expression in the cortex of TG mice, in comparison to age-matched wild-type control mice. CB2R expression changes were insignificant between the two groups, however, following CBD treatment, CB2R expression was significantly increased. Interestingly, we demonstrated PPARγ co-expressed with Aβ plaques in TG mice, and following CBD treatment, PPARγ co-expression increased. Lastly, we demonstrated dysregulations of the PI3K signaling pathway observed in TG mice was ameliorated with CBD treatment. In this study, we attributed the effects of CBD on AD-related biomarkers, particularly decreased Aβ plaque load and neuroinflammation, to the alterations in CB2R and PPARγ expression.},
}

Animals
*Cannabidiol/pharmacology/therapeutic use
Mice, Transgenic
*Plaque, Amyloid/drug therapy/metabolism
*Alzheimer Disease/drug therapy/metabolism
PPAR gamma/metabolism/genetics
Mice
Receptor, Cannabinoid, CB1/metabolism/genetics
Receptor, Cannabinoid, CB2/metabolism/genetics
Astrocytes/drug effects/metabolism
Glial Fibrillary Acidic Protein/metabolism/genetics
Amyloid beta-Peptides/metabolism
*Gliosis/drug therapy
Cerebral Cortex/metabolism/drug effects
Hippocampus/metabolism/drug effects
Amyloid beta-Protein Precursor/genetics

@article {pmid42893563,
year = {2026},
author = {Altas, B and Georgiou, P and Onisiforou, A},
title = {AI-bioinformatics synergy for precision medicine in brain diseases: integrating radiomics and multi-omics data.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {5},
pages = {},
pmid = {42893563},
issn = {1477-4054},
support = {//IDSA Foundation/ ; },
mesh = {Humans ; Radiomics ; *Precision Medicine/methods ; Multiomics ; *Computational Biology/methods ; *Artificial Intelligence ; *Brain Diseases/diagnostic imaging/genetics/metabolism ; Genomics ; Proteomics ; Brain Neoplasms/diagnostic imaging ; },
abstract = {The convergence of artificial intelligence (AI) and bioinformatics is reshaping the landscape of precision medicine in brain diseases, particularly in neurological diseases and brain tumors. Despite advances in both fields, the combined application of radiomics and multi-omics fusion remains underutilized, even though integrative frameworks are essential for addressing the complexity and heterogeneity of imaging and molecular data. This review examines how integrative AI-bioinformatics frameworks enable the fusion of radiomics with genomics, transcriptomics, proteomics, and other omics modalities to more comprehensively model disease complexity. Leveraging deep learning, graph neural networks, and advanced representation learning, these multimodal systems facilitate biomarker discovery, patient stratification, and personalized treatment strategies. We critically evaluate key challenges including data heterogeneity, limited interpretability, and barriers to clinical validation, and highlight emerging solutions aimed at enhancing reproducibility and translational readiness. Case studies in gliomas, Alzheimer's disease, and multiple sclerosis illustrate the clinical utility of unified imaging-omics architectures. Ultimately, this review positions radiomics and multi-omics integration as a foundational approach for the next generation of precision medicine in brain diseases by bridging the gap between computational innovation and clinical application.},
}

Humans
Radiomics
*Precision Medicine/methods
Multiomics
*Computational Biology/methods
*Artificial Intelligence
*Brain Diseases/diagnostic imaging/genetics/metabolism
Genomics
Proteomics
Brain Neoplasms/diagnostic imaging

@article {pmid42894266,
year = {2026},
author = {Hasegawa, C and Doi, Y and Hirano, T and Shirakawa, M and Tsuchiya, S and Yoshitsugu, H and Furihata, K and Miller, C and Singh, S and Cabalu, T and Yee, KL and Bueters, T and Alexopoulou, Z},
title = {A Phase 1 Study of MK-1942, a Negative Allosteric Modulator of mGluR2, in Healthy Japanese to Flexibly Assess Factors Including CYP2C19 Phenotype.},
journal = {Clinical and translational science},
volume = {19},
number = {11},
pages = {e70748},
pmid = {42894266},
issn = {1752-8062},
support = {//Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, New Jersey, USA/ ; },
mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Administration, Oral ; Allosteric Regulation/drug effects ; Area Under Curve ; *Cytochrome P-450 CYP2C19/genetics/metabolism ; Double-Blind Method ; Healthy Volunteers ; Japan ; Phenotype ; *Receptors, Metabotropic Glutamate/metabolism/antagonists & inhibitors ; East Asian People/genetics ; },
abstract = {MK-1942 is a negative allosteric modulator of the metabotropic glutamate receptor 2 that was investigated for the treatment of Alzheimer's disease and depression. Nonclinical studies with recombinant human CYPs and genotyped human hepatocytes suggested that CYP2C19 is involved in the metabolism of MK-1942. Given the high incidence of different CYP2C19 polymorphisms in the Japanese population, a Phase 1 single and multiple dose study in healthy Japanese participants provided an opportunity to determine the involvement of CYP2C19 phenotype on the clinical PK of MK-1942. Also, since a first-in-human study in non-Japanese showed a decrease in exposures after administration with high-fat meal, we further tested an effect of low-fat meal on PK in the Japan study. The study was designed with flexibility which enabled dose selection for the multiple dose panels, based on the totality of safety and PK data. Oral administration of single and multiple doses of MK-1942 in Japanese participants was generally well tolerated. AUC0-inf was comparable between fasted and fed (low-fat meal) state. Following a single dose of MK-1942, AUC0-inf was ~70% increased in CYP2C19 poor metabolizer (PM) vs. extensive metabolizer (EM). Therefore, a decision was made to test the multiple dose separately for each CYP2C19 phenotype, rather than grouping them into a single panel. As opposed to the expectation from the single dose result, steady state exposures were similar among CYP2C19 phenotypes. These data supported the subsequent global Phase 2 study to permit a low-fat meal around dosing and no dose adjustment for any CYP2C19 phenotype.},
}

Adult
Female
Humans
Male
Middle Aged
Young Adult
Administration, Oral
Allosteric Regulation/drug effects
Area Under Curve
*Cytochrome P-450 CYP2C19/genetics/metabolism
Double-Blind Method
Healthy Volunteers
Japan
Phenotype
*Receptors, Metabotropic Glutamate/metabolism/antagonists & inhibitors
East Asian People/genetics

@article {pmid42894468,
year = {2026},
author = {Markus, HS},
title = {Vascular dementia and vascular cognitive impairment-current treatments and future prospects.},
journal = {International journal of stroke : official journal of the International Stroke Society},
volume = {21},
number = {9},
pages = {1200-1210},
pmid = {42894468},
issn = {1747-4949},
mesh = {Humans ; *Dementia, Vascular/therapy/physiopathology ; *Cognition Disorders/therapy/etiology ; },
abstract = {Vascular cognitive impairment (VCI) and vascular dementia (VaD) represent a substantial and growing global health burden, yet remain under-recognized and comparatively under-researched. Two broad categories are post-stroke cognitive impairment, and VCI secondary to chronic cerebrovascular disease of which the most common cause is cerebral small vessel disease (SVD). In addition, cerebrovascular pathology frequently coexists with Alzheimer's disease (AD), increasing the probability that AD pathology will manifest as clinical dementia. Current management focuses primarily on prevention through modification of cardiovascular risk factors and lifestyle interventions. Intensive blood-pressure control has shown the strongest evidence, reducing future all-cause dementia while slowing progression of white-matter abnormalities. Multidomain lifestyle interventions incorporating exercise, diet, cognitive training, and vascular risk monitoring may also preserve cognition, although results across trials remain variable. In established VCI and VaD, treatment options are limited; cholinesterase inhibitors and memantine lack convincing evidence of benefit, and no pharmacological therapy has definitively demonstrated symptomatic improvement or delayed disease progression. Advances in understanding SVD and VCI pathophysiology are, however, identifying promising therapeutic targets. Emerging evidence highlights endothelial dysfunction, impaired cerebral autoregulation, increased blood-brain barrier permeability, inflammation, and glymphatic dysfunction as possible mechanisms underlying SVD. Current trials are evaluating treatment approaches based on this framework including cerebral vasodilators such as cilostazol, isosorbide mononitrate and phosphodiesterase-5 inhibitors, anti-inflammatory therapies, glucagon-like peptide-1 receptor agonists, remote ischemic conditioning, and strategies targeting glymphatic function. Improved mechanistic understanding, appropriately targeted interventions, and adequately powered long-term clinical trials are required to translate these emerging approaches into effective treatments for VCI and VaD.},
}

Humans
*Dementia, Vascular/therapy/physiopathology
*Cognition Disorders/therapy/etiology

@article {pmid42895147,
year = {2026},
author = {Chaudhary, S and Dhankhar, S and Saini, M and Singh, TG and Chauhan, S and Kumar, V},
title = {Mechanistic Evaluation of Psilocybin in Neurodegenerative Disorders: Relevance of 5-HT2A Receptors and Downstream Pathways.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273491538261009064612},
pmid = {42895147},
issn = {1996-3181},
abstract = {More than fifty million individuals worldwide are experiencing neurodegenerative disorders, which include Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and frontotemporal dementia. These disorders have a significant role in the gradual degradation of cognition and motor skills. Most current treatment approaches have little effect on changing the course of the disease and are largely symptomatic. Psilocybin, a naturally occurring tryptamine alkaloid from psilocybin mushrooms, has become a promising medicinal agent because of its hallucinogenic, neuroprotective, and neuroplastic properties. After being metabolically transformed into its active form, psilocin, it primarily activates serotonin 5-HT2A receptors. This modulates glutamatergic neurotransmission and neurotrophic signaling pathways such as BDNF/TrkB and mTOR, which regulate synaptic remodeling, dendritic complexity, neurogenesis, neuroinflammatory response, and default mode network connectivity, all of which are linked to depression and dementia. Preclinical research studies demonstrate that psilocybin increases hippocampal plasticity, restores dendritic complexity, lowers proinflammatory cytokine levels, and promotes fear extinction in experimental models of stress, ischemic stroke, and neurodegeneration. Emerging clinical studies also indicate that individuals with moderate cognitive impairment, early-onset Alzheimer's disease, and Parkinson's disease may see long-term decreases in anxiety and depression as well as improvements in cognitive function, frequently after a single dose administration. Additionally, psilocybin has demonstrated promise in treating mental comorbidities that often accompany neurodegenerative illness, such as treatment-resistant depression, drug use disorders, and obsessive-compulsive disorder. However, there are still significant obstacles to overcome, such as optimizing dosing schedules, assessing safety issues such as temporary perceptual abnormalities and cardiovascular consequences, and translating preclinical results into extensive phase -III clinical studies. This review incorporates the most recent data on psilocybin's chemistry, pharmacology, metabolism, and mechanistic actions; it highlights the drug's therapeutic potential across a variety of neurodegenerative diseases and emphasizes the necessity of carefully planned randomized controlled trials to determine clinical efficacy, long-term safety, and its place in multimodal treatment approaches.},
}

@article {pmid42895489,
year = {2026},
author = {Liang, X and Jiang, C and Zhug, H and Sun, Y and Tu, S and Kang, J},
title = {Deep Cervical Lymphaticovenous Anastomosis (LVA) for Alzheimer's Disease: A Case Report.},
journal = {Journal of perianesthesia nursing : official journal of the American Society of PeriAnesthesia Nurses},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jopan.2026.08.005},
pmid = {42895489},
issn = {1532-8473},
abstract = {This case report describes the short-term observed clinical course of a 65-year-old patient with Alzheimer's disease (AD) who underwent deep cervical lymphaticovenous anastomosis (LVA) under general anesthesia, and summarizes the perianesthesia nursing care provided before, during, and after anesthesia. Neuropsychological assessments showed limited changes in cognitive scores at 1 month after surgery, including a 1-point increase in MMSE and a 1-point decrease in ADAS-Cog, while ADCS-ADL declined. The NPI score decreased from 21 preoperatively to 0 on postoperative day 3 and remained lower than baseline, with a score of 2 at 1 month. Given the single-case design, short follow-up period, and lack of a control condition, these observations should be interpreted cautiously and cannot establish treatment efficacy. Deep cervical LVA may warrant further investigation as an exploratory surgical approach for AD, and perianesthesia nursing care may support perioperative safety, recovery, and complication prevention in this context. Further controlled studies with longer follow-up are needed.},
}

@article {pmid42897209,
year = {2026},
author = {Santoro, JD and Abdel-Latif, S and Banerjee, AK and Mager, H and Silverman, M and Kazerooni, L and Otey, ST and Yousuf, MM and Lucas, MC and Schlachetzki, Z and Rissman, RA and Rafii, MS},
title = {Phosphorylated tau 217 in young adults with Down syndrome and Down syndrome regression disorder.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
pmid = {42897209},
issn = {2730-664X},
support = {K23 HL155898/HL/NHLBI NIH HHS/United States ; K23HL155898//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
abstract = {BACKGROUND: Down syndrome regression disorder (DSRD) causes a rapid loss of cognitive, behavioral, and daily living skills, usually in adolescents and young adults with Down syndrome. Because people with Down syndrome have a high lifetime risk of Alzheimer's disease, we examined whether DSRD is associated with an Alzheimer-related pattern of tau pathology.

METHODS: In this prospective, single-center study, we measured plasma phosphorylated tau-217 (p-tau217), a blood marker of Alzheimer pathology, in 132 participants: 48 with DSRD, 39 with Down syndrome without regression (DSwR), and 45 neurodevelopmental controls. We compared p-tau217 concentrations across groups and examined relationships with demographic factors, medical conditions, treatment status, and diagnostic test abnormalities.

RESULTS: Median p-tau217 concentrations were similar in the DSRD (0.082 pg/mL), DSwR (0.084 pg/mL), and neurodevelopmental control (0.080 pg/mL) groups (overall comparison, p  =  0.57). Pairwise comparisons and models accounting for demographic and clinical factors also showed no statistically significant group differences. Among participants with DSRD, p-tau217 was not associated with treatment status or abnormalities on brain-wave testing, neuroimaging, or cerebrospinal fluid analysis. No clinical or demographic factor remained associated with p-tau217 after accounting for the number of analyses performed.

CONCLUSIONS: These findings provide no evidence of a group-level Alzheimer-related p-tau217 elevation in young people with DSRD and support DSRD as a condition distinct from Alzheimer's disease. However, a single blood measurement cannot exclude Alzheimer pathology in an individual. Longitudinal studies using several complementary biomarkers are needed.},
}

@article {pmid42897323,
year = {2026},
author = {Armbrust, F and Bruhn, H and Bickenbach, K and Steen, N and Shcoory, S and Afratis, N and Korn, N and Körschgen, H and Moali, C and Pietrzik, CU and Sagi, I and Becker-Pauly, C},
title = {Meprin β is specifically inhibited by its cognate synthetic propeptide.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {83},
number = {1},
pages = {},
pmid = {42897323},
issn = {1420-9071},
mesh = {*Metalloendopeptidases/antagonists & inhibitors/metabolism ; Humans ; Animals ; *Protease Inhibitors/pharmacology/chemistry ; *Peptides/pharmacology/chemistry/chemical synthesis ; Mice ; Hydroxamic Acids/pharmacology ; },
abstract = {Meprin β is a zinc-dependent metalloprotease of the astacin family highly expressed in kidney and intestine. Dysregulation of meprin β expression and activity was observed in several pathological conditions such as Alzheimer's disease, cancer, fibrosis, and inflammatory bowel disease. Therefore, inhibition of meprin β could be a promising therapeutic option to treat pathological conditions influenced by this protease. However, available small-molecule compounds such as the broad-spectrum metalloproteinases inhibitors marimastat or actinonin lack specificity. Hence, more selective meprin β inhibitors needs to be developed. Here, we provide evidence that the synthetically generated cognate meprin β propeptide serves as highly specific inhibitor for the protease (IC50 = 1.35 µM), while other related metalloproteases such as meprin α and a disintegrin and metalloproteinases (ADAMs) are not affected. Employing a targeted approach revealed that removal of the last four C-terminal amino acids of the propeptide significantly improved its inhibitory capacity (IC50 = 0.68 µM). In cell-based experiments, treatment with the propeptide resulted in diminished meprin β activity and decreased cleavage of its substrates, including the interleukin-6 receptor (IL-6R) and the G protein-coupled receptor latrophilin-3 (LPHN3). Suitability was further confirmed in ex vivo cultivated organotypic brain slices, where the administration of the propeptide also resulted in decreased meprin β activity and diminished latrophilin-3 cleavage. Thus, not only the synthetic wildtype propeptide but especially a C-terminally truncated propeptide of meprin β represent highly specific inhibitors with potential for therapeutic application.},
}

*Metalloendopeptidases/antagonists & inhibitors/metabolism
Humans
Animals
*Protease Inhibitors/pharmacology/chemistry
*Peptides/pharmacology/chemistry/chemical synthesis
Mice
Hydroxamic Acids/pharmacology

@article {pmid42897722,
year = {2026},
author = {Grewal, P and Seidman, MB and Chasen, J and Lench, D and Dickens, I and Brennan, EA and Rodriguez-Porcel, F and Kindred, J and George, MS and Kautz, S and Caulfield, KA and McTeague, LM},
title = {Brain Stimulation as a Treatment for Apathy: A Scoping Review of Effects and Safety.},
journal = {The Journal of neuropsychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {appineuropsych20250297},
doi = {10.1176/appi.neuropsych.20250297},
pmid = {42897722},
issn = {1545-7222},
abstract = {OBJECTIVE: Apathy is a neuropsychiatric syndrome characterized by impairment of goal-directed behavior, cognition, and emotional responsiveness. In this scoping review, the authors evaluated the literature on brain stimulation for the treatment of patients with apathy across diagnostic categories and provide recommendations to guide future research and practice.

METHODS: The authors searched PubMed, Scopus, and PsycInfo for studies involving brain stimulation for apathy as a primary or secondary outcome.

RESULTS: From 1,209 records, 52 studies evaluating brain stimulation were included; of these, 10 systematic reviews or meta-analyses were synthesized separately. Modalities included repetitive transcranial magnetic stimulation (rTMS; N=26), deep brain stimulation (DBS; N=7), transcranial direct current stimulation (tDCS; N=6), electroconvulsive therapy (N=1), transcranial alternating current stimulation (N=1), and transcranial pulsating electromagnetic field therapy (N=1). Populations included patients with schizophrenia (N=477), Parkinson's disease (PD; N=289), depression (N=288), Alzheimer's disease (AD) and mild cognitive impairment (MCI) (N=210), Huntington's disease (N=42), PD with MCI (N=28), traumatic brain injury (N=28), stroke (N=14), COVID-19 (N=12), and dementia with Lewy bodies (N=6) (total N=1,366). rTMS improved apathy measures, most consistently in AD, with positive trends in depression, MCI, stroke, and schizophrenia. tDCS showed variable effects, with some benefits for schizophrenia. DBS showed mixed results, varying with stimulation location. Observed adverse events were mild and modality specific.

CONCLUSIONS: Investigations into brain stimulation as a treatment for apathy show some promise. Conclusions were limited by small sample sizes, heterogeneous study designs, and variable outcome measures. Randomized trials with common validated apathy instruments, standardized stimulation parameters, and harmonized diagnostic measures may help advance the field.},
}

@article {pmid42897836,
year = {2026},
author = {Kumari, P and Sathyanarayanan, A and Pimpalkar, K and Kumar, A and Kumar, D and Chopade, S},
title = {Design, In Silico Targeting, and Characterization of Curcumin-Ibuprofen Prodrug Microspheres for Brain-Specific Delivery in Alzheimer's Therapy.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128447768260915075822},
pmid = {42897836},
issn = {1873-4286},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a complex neurodegenerative condition characterized by limited treatment effectiveness, attributed to inadequate Blood-Brain Barrier (BBB) permeability and low medication absorption. Curcumin and ibuprofen possess anti-inflammatory and neuroprotective properties but are limited by pharmacokinetic constraints. This study aimed to synthesize a curcumin-ibuprofen mutual prodrug (CIP), formulate it into chitosan-based microspheres (CIPM), and evaluate its neuroprotective potential for brain-targeted delivery in AD.

METHODS: CIP was synthesized via ethylenediamine carbodiimide (EDCI) mediated esterification and confirmed through IR, NMR, LC-MS, and DSC. CIPM microspheres were prepared using emulsion crosslinking, characterized by scanning electron microscopy, drug entrapment efficiency (85.5%), zeta potential, particle size analysis, and DSC. In silico tools (SwissADME, ProTox-II) and molecular docking were used to assess ADMET profiles and target binding (AChE, BACE1, β-secretase). Network pharmacology identified overlapping targets between curcumin and AD. In vivo evaluation was conducted in a TMT (Trimethyltin)- induced neurodegeneration rat model through behavioral Morris Water Maze (MWM), Novel Object Recognition (NOR), Social Recognition Test (SRT), and biochemical and histological assessments.

RESULTS: CIP demonstrated strong binding affinity with AD-related targets (-10.0 to -8.5 kcal/mol) and favorable ADMET properties. Network analysis identified 226 overlapping targets and key hub genes. CIPM significantly improved cognitive performance, antioxidant enzyme levels, and neuronal integrity compared to individual drugs and showed comparable efficacy to donepezil.

DISCUSSION: The present study demonstrates that the curcumin-ibuprofen conjugate, when delivered through chitosan-based microspheres, effectively enhances brain targeting and overcomes pharmacokinetic barriers. The formulation not only improved drug bioavailability but also showed superior neuroprotective and cognitive benefits compared to individual drugs. Molecular docking and network pharmacology further confirmed its multi-target potential, suggesting a synergistic mechanism in modulating key AD pathways. These outcomes highlight CIPM as a promising candidate that warrants further pharmacokinetic and clinical validations for Alzheimer's therapy.

CONCLUSION: The curcumin-ibuprofen prodrug-loaded microspheres present a promising brain-targeted treatment approach for Alzheimer's disease by improving bioavailability, engaging multiple targets, and providing neuroprotection.},
}

@article {pmid42898005,
year = {2026},
author = {Rosenberg, A and Rennie, A and Ekman, U and Daniilidou, M and Hall, A and Matton, A and Solomon, A and Wahlund, LO and Kivipelto, M and Westman, E},
title = {Real-World Patient Eligibility for Alzheimer's Disease Anti-Amyloid Therapy in Seven Swedish Memory Clinics.},
journal = {European journal of neurology},
volume = {33},
number = {10},
pages = {e70786},
pmid = {42898005},
issn = {1468-1331},
support = {101112145//Innovative Health Initiative/ ; 101132933//Innovative Health Initiative/ ; //Region Stockholm (ALF)/ ; FoUI-104172//Center for Innovative Medicine/ ; 357810//EU Joint Programme - Neurodegenerative Disease Research/ ; AF-1031812//Alzheimerfonden/ ; 2025-02405//Vetenskapsrådet/ ; //Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; FO2026-0228//Hjärnfonden/ ; 2025-02071//Forskningsrådet om Hälsa, Arbetsliv och Välfärd/ ; 2025-03749//VINNOVA/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/cerebrospinal fluid ; Sweden ; Female ; Male ; Aged ; *Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; *Cognitive Dysfunction/drug therapy/cerebrospinal fluid ; *Eligibility Determination ; Cohort Studies ; },
abstract = {BACKGROUND: Anti-amyloid therapies lecanemab and donanemab are the first potentially disease-modifying treatments for Alzheimer's disease (AD) approved in Europe. We estimated real-world eligibility for these treatments in a large multicenter memory clinic patient cohort in Sweden (MemClin).

METHODS: MemClin included patients with a first diagnostic visit between 2016 and 2022 at seven specialist memory clinics in Stockholm, Sweden. To estimate eligibility for anti-amyloid therapy, we applied key inclusion/exclusion criteria from the lecanemab and donanemab appropriate use recommendations. Eligible patients were required to have (1) a clinical diagnosis of AD-type dementia or mild cognitive impairment (MCI), (2) confirmed Aβ pathology (abnormal CSF Aβ42) and (3) no apparent medical exclusion criteria. Eligibility was calculated for different scenarios to provide both upper-bound estimates (main analysis) and more conservative, implementation-ready estimates of near-term treatable patients (sensitivity analysis).

RESULTS: Cohort consisted of 2126 patients (mean age 77.1 ± 6.6 years; 61.8% MCI, 24.2% dementia, 13.7% subjective cognitive impairment). In the main analysis, 11.5% of the whole cohort was estimated to be eligible for either treatment (lecanemab 10.6%, donanemab 11.5%). Most eligible patients had early-stage disease (61.9% MCI vs. 38.1% dementia) and an A + T- biomarker profile, that is, normal biomarker of tau (57.9%). Eligibility was markedly lower in sensitivity analyses (e.g., 2.7% when all patients without MRI were assumed ineligible).

CONCLUSIONS: Even upper-bound estimates indicate that a minority of real-world memory clinic patients may currently qualify for anti-amyloid therapy. These findings provide timely evidence to inform the ongoing debate on the implementation of anti-amyloid therapy in public healthcare.},
}

Humans
*Alzheimer Disease/drug therapy/cerebrospinal fluid
Sweden
Female
Male
Aged
*Amyloid beta-Peptides/cerebrospinal fluid
Aged, 80 and over
*Cognitive Dysfunction/drug therapy/cerebrospinal fluid
*Eligibility Determination
Cohort Studies

@article {pmid42898907,
year = {2026},
author = {Wicker, A and Courtright-Lim, A and Tilburt, J},
title = {Ethical challenges in the clinical translation of anti-amyloid monoclonal antibodies for Alzheimer's disease: a scoping review.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1953954},
pmid = {42898907},
issn = {1664-0640},
abstract = {BACKGROUND: The development and evaluation of anti-amyloid beta monoclonal antibodies (mAbs) for the treatment of Alzheimer's disease have been accompanied by extensive ethical debate spanning clinical trials, regulatory processes, prescribing practices, and healthcare delivery. This scoping review examined literature published between 2006 and 2026 to identify and clarify the landscape of ethical considerations surrounding the implementation, prescribing, and delivery of anti-amyloid mAbs across both research and clinical settings.

METHODS: We searched PubMed, Scopus, Web of Science, Embase, and Ovid EBM Reviews (including CENTRAL and CDSR) from 2006 to March 2026 using a structured search strategy. Eligible publications focused on ethical issues associated with the clinical translation of anti-amyloid mAbs. Two reviewers independently screened titles, abstracts, and full-text articles, with duplicate extraction performed on an initial subset of publications. The review was conducted using JBI guidance and reported according to PRISMA-ScR.

RESULTS: We identified 84 publications from 23 countries published between 2014 and 2026, including 12 original research studies, 1 systematic review, and 71 commentaries, narrative reviews, legal analyses, or practice guidelines. Analysis identified 32 subthemes, which were synthesized into 7 overarching themes: (1) beneficence and nonmaleficence, (2) respect for persons, (3) equity and accessibility, (4) evidence and trial integrity, (5) governance and stewardship, (6) relational and social impacts, and (7) health system readiness and sustainability. Among the 32 subthemes, uncertain clinical benefit and risk of harm (both within the beneficence and nonmaleficence theme) were discussed most frequently within the literature, each appearing in 61 publications.

CONCLUSIONS: The biomedical literature documents a broad range of ethical considerations relating to anti-amyloid mAbs. Despite this growing literature, it is primarily based on commentary, with few empirical studies, and even fewer incorporating the perspectives of patients, families, and clinicians. Doing so may add further context and nuance to ethical discussion about mAbs in the years ahead.},
}

@article {pmid42899916,
year = {2026},
author = {Vasenina, EE},
title = {[Mild cognitive impairment as a heterogeneous condition: From diagnostic algorithm - to individualized therapeutic approaches].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {9},
pages = {42-51},
doi = {10.17116/jnevro202612609142},
pmid = {42899916},
issn = {1997-7298},
mesh = {Humans ; *Cognitive Dysfunction/diagnosis/drug therapy/etiology/therapy/epidemiology ; Disease Progression ; Algorithms ; Neuropsychological Tests ; Risk Factors ; Precision Medicine ; Dementia/etiology/prevention & control ; },
abstract = {Mild cognitive impairment (MCI) is a prevalent syndrome affecting approximately 10-15% of the global population. In the Russian Federation, the estimated number of individuals with MCI may reach 5 million, with continued growth projected. Subjective cognitive deficits are linked to an increased risk of dementia, although memory complaints are often regarded as a normal aspect of aging. Standard neuropsychological assessments, including the Mini-Mental State Examination (MMSE), Mini-Cog, and Montreal Cognitive Assessment (MoCA), often lack sufficient sensitivity to detect MCI, particularly in individuals with high cognitive reserve. MCI has multiple etiologies, including depression and other affective disorders, severe somatic diseases, traumatic or toxic brain injury, and neurodegenerative or vascular pathologies of the central nervous system. This etiological diversity leads to variable clinical outcomes: cognitive function may return to age-appropriate norms in some instances, while in others, early impairment progresses to dementia. High-risk factors for conversion from MCI to dementia include the amnestic subtype of cognitive impairment, slow gait, coexisting affective disorders, sensory deficits, senile preasthenia and asthenia, and sleep disturbances. Accurate prediction of disease progression is critical for informing therapeutic strategies. For patients at elevated risk of progression, pharmacological interventions should be selected not only for symptomatic management but also for their potential to delay conversion. In Russia, Miladean, a combination of memantine and melatonin, is approved for use in patients with MCI. In addition to its symptomatic benefits, Miladean exhibits neuroprotective and endothelioprotective properties, supporting its use as the preferred treatment for patients at high risk of MCI progression.},
}

Humans
*Cognitive Dysfunction/diagnosis/drug therapy/etiology/therapy/epidemiology
Disease Progression
Algorithms
Neuropsychological Tests
Risk Factors
Precision Medicine
Dementia/etiology/prevention & control

@article {pmid42900219,
year = {2026},
author = {Giri, N and Chakraborty, A},
title = {Nanomaterial Design for Macrophage Reprogramming: Emerging Strategies and Mechanistic Insights for Inflammation and Tumor Therapy.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.6c01937},
pmid = {42900219},
issn = {2576-6422},
abstract = {Macrophages play a paradoxical role in inflammation and tumor. They can protect the host during acute inflammation but act as the main driver for the chronic inflammation which is a common characteristic of several diseases including rheumatoid arthritis, atherosclerosis, type 2 diabetes, inflammatory bowel disease, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In the tumor microenvironment, macrophages switch their phenotype to the immunosuppressive M2 state that promotes tumor growth, angiogenesis, and metastasis. Emerging nanomaterial platforms are trying to offer transformative solutions by enabling the precise delivery of immunomodulatory drugs directly to disease-site macrophages. This review will provide comprehensive comparative analysis of these emerging nanomaterial designs strategies across two disease paradigms: inflammatory diseases and tumor. The discussion will focus on various strategies which include inhibiting chemokine axis (CCL2-CCR2 axis), selective elimination of macrophages through apoptosis, metabolic reprogramming, biomimetic and apoptotic cell-inspired nanoparticles leveraging natural macrophage clearance pathways to promote M2 polarization in inflammation, and the activation of tumor-associated macrophages via TLR and STING agonist. We highlight the role of nanoparticle surface chemistry, composition, and targeting ligands in achieving the two opposite therapeutic outcomes of these two diseases while maintaining some common design principles including EPR-mediated accumulation at the disease sites and biomimetic modifications. We also mentioned novel next-generation nanoparticle-based platforms that are currently in clinical trials for the treatment of tumor and inflammatory diseases. Finally, we discuss the barriers that limit the clinical translational potential of broad nanoparticles, with particular emphasis on nanoparticle-related immunotoxicity, macrophage heterogeneity, and manufacturing reproducibility of the nanoparticles.},
}

@article {pmid42900250,
year = {2026},
author = {Páez, A and Piñol-Ripoll, G and Dakterzada, F and Dang-Vu, TT},
title = {Sleep Spindles and Slow Oscillations as Potential Biomarkers and Therapeutic Targets in Mild-to-Moderate Alzheimer's Disease.},
journal = {Current neurology and neuroscience reports},
volume = {26},
number = {1},
pages = {},
pmid = {42900250},
issn = {1534-6293},
mesh = {Humans ; *Alzheimer Disease/physiopathology/therapy/diagnosis ; Biomarkers ; *Sleep/physiology ; Animals ; },
abstract = {PURPOSE OF REVIEW: This review critically evaluates evidence on sleep spindles (SP), slow oscillations (SOs), and their coordination in mild-to-moderate Alzheimer's disease (AD), focusing on their relationships with cognition, AD biomarkers, and their therapeutic potential.

RECENT FINDINGS: Longitudinal studies associate greater SP and/or SO activity with better cognition and favourable amyloid and tau profiles after clinical onset. Spindle and SO coupling may index network integrity. Preserved NREM sleep oscillations are associated with lower orexin concentrations and weaker adverse relationships between orexin and cognitive and neuropsychiatric outcomes. Closed-loop acoustic stimulation and slow-oscillatory transcranial direct-current stimulation can modify SO activity, spindle activity, and coupling, although cognitive and biomarker benefits remain uncertain. Spindle-SO activity, including their temporal coupling, are associated with cognition and AD biomarkers across the disease continuum. Closed-loop acoustic and electrical stimulation can modify these oscillations, but biomarker-characterized trials in MCI and AD are needed to determine whether treatment produces durable cognitive and biomarker benefits.},
}

Humans
*Alzheimer Disease/physiopathology/therapy/diagnosis
Biomarkers
*Sleep/physiology
Animals

@article {pmid42901167,
year = {2026},
author = {Perneczky, R and Schöll, M and Rauchmann, BS and Hofmann, A},
title = {More than just accuracy: A pathway-level framework for implementing blood and digital biomarkers for Alzheimer's disease care.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.09.006},
pmid = {42901167},
issn = {1097-4199},
abstract = {Blood biomarkers are transforming Alzheimer's disease diagnostics by enabling a scalable, minimally invasive assessment of pathology. Food and Drug Administration clearances and European market certifications of different plasma tests mark a shift toward biological diagnosis in routine care. However, clinical implementation is not guided by diagnostic accuracy alone but will depend on improved patient-centered and pathway-level outcomes, including diagnostic confidence, the appropriate use of CSF and PET assessments, time to diagnosis, amyloid-targeting treatment eligibility assessment, and trial recruitment. Digital biomarkers may complement blood tests by providing repeated measures of cognition, speech, and mobility. Yet, their evidence base remains more heterogeneous regarding construct validity, supervision requirements, device dependence, adherence burden, cultural portability, interpretability, and regulatory classification. This review defines how combined blood-digital workflows could be evaluated beyond accuracy, including the context of use, downstream decisions, ethical aspects, governance, and post-market monitoring, ultimately aiming to translate biomarker innovation into meaningful benefits for patients and health systems.},
}

@article {pmid42901789,
year = {2026},
author = {Maekawa, H},
title = {[Intravenous Thrombolysis for Acute Ischemic Stroke: Current Evidence and Perspectives].},
journal = {No shinkei geka. Neurological surgery},
volume = {54},
number = {5},
pages = {996-1004},
doi = {10.11477/mf.030126030540050996},
pmid = {42901789},
issn = {0301-2603},
mesh = {Humans ; Administration, Intravenous ; *Brain Ischemia/drug therapy ; Fibrinolytic Agents/administration & dosage/therapeutic use ; *Ischemic Stroke/drug therapy ; *Thrombolytic Therapy/methods ; Tissue Plasminogen Activator/therapeutic use/administration & dosage ; },
abstract = {Since its introduction, intravenous thrombolysis (IVT) with alteplase has remained a mainstay of reperfusion therapy in the hyperacute management of acute ischemic stroke (AIS). Recent clinical evidence has driven a major paradigm shift from a strictly "time-based" approach to a "tissue-based" approach. Advanced neuroimaging techniques, including diffusion-weighted imaging-fluid-attenuated inversion recovery (DWI-FLAIR mismatch) and perfusion mismatch analyses, have enabled extension of the treatment window beyond 4.5 h and treatment of patients with strokes of unknown onset, particularly benefiting those who are ineligible for endovascular thrombectomy (EVT). Furthermore, the treatment criteria have been refined to recommend IVT for disabling deficits regardless of the baseline stroke severity score while withholding it from patients with minor, nondisabling presentations. An emerging challenge in clinical practice is determining whether IVT should be contraindicated in patients receiving novel amyloid-targeting therapies for Alzheimer's disease. Meanwhile, prehospital protocols involving mobile stroke units (MSUs) may help reduce onset-to-needle time in selected regions. IVT continues to evolve through personalized patient selection aimed at maximizing safety and improving functional outcomes.},
}

Humans
Administration, Intravenous
*Brain Ischemia/drug therapy
Fibrinolytic Agents/administration & dosage/therapeutic use
*Ischemic Stroke/drug therapy
*Thrombolytic Therapy/methods
Tissue Plasminogen Activator/therapeutic use/administration & dosage

@article {pmid42885677,
year = {2026},
author = {Pandey, JP},
title = {Immunoglobulin GM (γ marker) allotypes as potential genetic markers of efficacy of lecanemab therapy in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261500140},
doi = {10.1177/13872877261500140},
pmid = {42885677},
issn = {1875-8908},
abstract = {Lecanemab is a humanized IgG1 monoclonal antibody that targets amyloid-β (Aβ) aggregates, a pathological hallmark of Alzheimer's disease (AD). In the largest clinical trial of its kind to date, lecanemab slowed cognitive decline by 27% in patients with early-stage AD. Lecanemab has also been shown to reduce cerebral Aβ deposition. Lecanemab expresses the immunoglobulin GM 3 allotype, which is defined by an arginine residue in the CH1 region of the γ1 chain and is potentially immunogenic in individuals who lack this allotype. I hypothesize that anti-GM 3 antibodies, generated either following lecanemab administration or acquired previously through maternal-fetal incompatibility or transfusion of allotype-incompatible blood products, may form immune complexes with the therapeutic antibody. These immune complexes could be cleared by phagocytic cells, including microglia, thereby reducing the availability and efficacy of lecanemab and contributing to therapeutic nonresponsiveness. If validated, GM allotypes could serve as genetic markers for predicting response to lecanemab therapy and may help guide personalized treatment strategies in AD.},
}

@article {pmid42885691,
year = {2026},
author = {Alavi, A and Høilund-Carlsen, PF},
title = {The critical role of PET-based assessment of cerebrovascular disease in the management of patients with cognitive impairment and dementias.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497232},
doi = {10.1177/13872877261497232},
pmid = {42885691},
issn = {1875-8908},
abstract = {A recent survey provides valuable insights into French practitioners' preparedness for implementing anti-amyloid immunotherapy (AAI) for Alzheimer's disease. It highlights the need for education but also underscores a broader challenge: clinicians must understand not only treatment protocols but also unresolved issues regarding diagnostic specificity, efficacy, safety, and cost-effectiveness. Amyloid biomarkers should not be considered definitive indicators of disease causality or treatment response. Greater attention should also be given to functional imaging approaches and cerebrovascular pathology, which may contribute to a more comprehensive understanding of cognitive decline. A balanced, evidence-based approach is essential before widespread adoption of AAI.},
}

@article {pmid42885915,
year = {2026},
author = {Gries, M and Schäfer, KH and Endres, K},
title = {Targeting the microbiota-gut-brain axis in Alzheimer's and Parkinson´s disease: recent therapeutic approaches.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2026.2748747},
pmid = {42885915},
issn = {1744-7631},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders with limited disease-modifying treatment options. Evidence suggests that the microbiota-gut-brain axis (MGBA) plays a role in these diseases by facilitating communication between the gut and the central nervous system. Associations have been found between altered gut microbiota composition and function, impaired barrier integrity, dysregulated metabolite production, and immune activation to neuroinflammation and progressive neurodegeneration.

AREAS COVERED: This review summarizes and critically assesses recent studies from the past year to provide an updated overview of therapeutic strategies targeting the MGBA in both diseases. We discuss dietary interventions, probiotics, postbiotics, microbial metabolites, and approaches targeting gut barrier function. We also highlight strategies such as fecal transplantation, photobiomodulation, and PD-targeted metabolism therapies using butyrate and resistant starch.

EXPERT OPINION: While these interventions have shown promising results in preclinical and early clinical trials, their clinical application is limited by methodological heterogeneity, interindividual variability and a lack of standardized protocols. Successful implementation requires carefully designed clinical trials, particularly longitudinal studies of presymptomatic cohorts, standardized microbiome analyses, and integrated multi-omics approaches to elucidate causal relations and facilitate personalized treatment strategies.},
}

@article {pmid42887669,
year = {2026},
author = {Otto, B and Zantvoord, JB and Siskind, D and Vermeulen, JM},
title = {Modulating neuroinflammation with glucagon-like peptide-1 receptor agonists: a scoping review exploring their therapeutic potential in schizophrenia.},
journal = {Progress in neuro-psychopharmacology & biological psychiatry},
volume = {},
number = {},
pages = {111978},
doi = {10.1016/j.pnpbp.2026.111978},
pmid = {42887669},
issn = {1878-4216},
abstract = {Neuroinflammation is a key contributor to the pathophysiology and symptomatology of schizophrenia spectrum disorders. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), clinically approved anti-diabetic and -obesity medication, have been associated with anti-inflammatory properties. It remains unclear whether GLP-1RA treatment can improve neuroinflammation within psychiatric disorders, including schizophrenia. This scoping review synthesizes evidence from clinical and preclinical studies on the anti-inflammatory effects of GLP-1RAs in psychiatric, neurodegenerative and neurological disease models, identifying crucial research gaps and providing future recommendations to guide potential clinical translation. The literature search was conducted in PubMed, Embase and PsycINFO and included outcomes of cytokine levels within blood and brain samples. Within the 40 included studies, two were clinical (schizophrenia and alcohol-use disorder) and 38 were preclinical models of psychiatric diseases, Alzheimer's -, Parkinson's Disease, Multiple Sclerosis, Epilepsy and lipopolysaccharide (LPS)-induced neuroinflammation. Preclinical studies showed anti-(neuro)inflammatory effects of GLP-1RAs, whereas the two available clinical studies found no significant changes in peripheral inflammatory markers. As these trials were not primarily designed or powered to test neuroinflammatory effects, the clinical findings remain inconclusive. Differences in study design, inflammatory measurements, pharmacokinetics and dosing may have contributed to the discrepancy between preclinical and clinical findings. Future research should prioritize early-phase dose-finding trials in non-diabetic, or -overweight patients diagnosed with schizophrenia spectrum disorders, evaluating the effects of alternative GLP-1RA regimens on neuroinflammatory markers, safety and clinical symptomatology. This is an essential step to determine their potential mental health-enhancing effects through the modulation of neuroinflammation within schizophrenia spectrum disorders.},
}

@article {pmid42887705,
year = {2026},
author = {Roy, J and Tsui, KC and Poon, CH and Zhang, J and Lai, Y and Wong, KY and Mihardja, M and Tse, V and Li, PC and Au, C and Ng, J and Kocabicak, E and Aquili, L and Wong, KH and Lu, Z and Temel, Y and Fung, ML and Lim, LW},
title = {Melatonin ameliorates behavioral deficits in 5xFAD mice through modulation of neurogenesis, neuroimmune responses, neurotransmission, and metabolic pathways.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {107077},
doi = {10.1016/j.bbi.2026.107077},
pmid = {42887705},
issn = {1090-2139},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with limited disease-modifying treatment options. Melatonin, an endogenous hormone, has been shown to have therapeutic effects on amyloid deposition, oxidative stress, and neuroinflammation in AD. However, the mechanisms of its neuroprotective effects in the hippocampus remain largely unknown. This study aimed to investigate the multi-mechanistic neuroprotective effects of melatonin in AD. Eight-month-old female 5xFAD transgenic mice were treated with melatonin (10 mg/kg) for 4 weeks. Temozolomide and bromodeoxyuridine were used to block neurogenesis and to label proliferating neurons, respectively. Our results showed that 5xFAD mice treated with melatonin exhibited improved exploratory behavior, enhanced memory performance, reduced depressive-like symptoms, and decreased levels of stress hormones. At the molecular level, melatonin reduced amyloid-beta (Aβ) plaque accumulation, elevated hippocampal neurogenesis markers (DCX and BrdU), increased Trem2 expression and anti-inflammatory microglial activation, restored serotonergic, dopaminergic, catecholaminergic, and GABAergic neurotransmission, and partially normalized broader hippocampal metabolic pathways. Notably, temozolomide treatment abrogated the beneficial effects of melatonin on memory performance and depressive-like behavior in 5xFAD mice, indicating a neurogenesis-dependent mechanism. Collectively, these findings suggest that melatonin ameliorates behavioral deficits in 5xFAD mice through both neurogenesis-independent (reduced Aβ plaque accumulation, Trem2-microglial activation, neurotransmission restoration, and metabolic remodeling) and hippocampal neurogenesis-dependent mechanisms. Overall, melatonin holds therapeutic potential for attenuating the neuropathology and behavioral deficits in AD.},
}

@article {pmid42888370,
year = {2026},
author = {Porsteinsson, AP and Chumki, SR and Palma, AM and Zhang, Z and Wang, D and Such, P and Montano, CB},
title = {Brexpiprazole for Individual Agitation Symptoms in Alzheimer's Dementia: A Caregiver-Centered Post Hoc Analysis.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42888370},
issn = {2193-8253},
abstract = {INTRODUCTION: People with Alzheimer's dementia commonly experience agitation symptoms, which are distressing to caregivers and can influence long-term care decisions. The aim of this exploratory post hoc analysis was to test the hypothesis that brexpiprazole can improve individual agitation symptoms over 12 and 24 weeks, including symptoms that caregivers find the most distressing.

METHODS: Data were included from two phase 3, 12-week, randomized (brexpiprazole or placebo), double-blind trials and a phase 3, 12-week, brexpiprazole-treatment extension trial. Participants had Alzheimer's dementia with agitation, and lived at home or in long-term care. The frequency of 29 agitation symptoms over 12 and 24 weeks was assessed using Cohen-Mansfield Agitation Inventory (CMAI) item scores. The focus of this post hoc analysis was the 11 CMAI agitation symptoms that caregivers found the most distressing in a prior survey.

RESULTS: Among 610 participants (median age 74 years, 55.5% female, 44.5% male), each of the 11 most-distressing agitation symptoms reduced in frequency from baseline to Week 12, with further improvements to Week 24 (n = 159). Improvements over 12 weeks were numerically greater with brexpiprazole 2 or 3 mg/day (n = 363) compared with placebo (n = 247) on 9 of 11 symptoms: cursing or verbal aggression, spitting, repetitive sentences or questions, hitting, constant unwarranted requests for attention/help, trying to get to a different place, pacing or aimless wandering, grabbing onto people or things, and kicking. Each of the 18 other agitation symptoms (beyond the most distressing) also reduced in frequency. After 24 weeks, 15 of 29 agitation symptoms occurred less than once a week.

CONCLUSION: Brexpiprazole was associated with improvement in a range of agitation symptoms in people with Alzheimer's dementia, including those that are the most distressing to caregivers. These exploratory results suggest that brexpiprazole may improve the specific agitation symptoms that can have the biggest impact on the caregiver experience.

TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01862640, NCT03548584, NCT03594123.},
}

@article {pmid42889642,
year = {2026},
author = {Wenhua, Y and Wenjing, M and Yan, D and Fei, L and Juan, C and Xia, T and Yu, G and Xin, L and Yanlin, H and Ya, G and Xuelin, Y and Jing, L and Meimin, J and Wenyi, L and Yilin, K and Hongke, L and Yating, L},
title = {Should ApoE4 gene editing therapy be approached with caution when AD is accompanied by retinal neurodegenerative diseases?.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1934307},
pmid = {42889642},
issn = {1664-2295},
mesh = {Humans ; *Apolipoprotein E4/genetics ; *Gene Editing/methods ; *Alzheimer Disease/genetics/therapy/complications ; *Genetic Therapy/methods ; Animals ; *Neurodegenerative Diseases/genetics/therapy/complications ; *Retinal Diseases/genetics/therapy/complications ; Macular Degeneration/genetics/therapy ; },
abstract = {Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for Alzheimer's disease (AD), and ApoE4-directed gene editing and gene therapy have emerged as promising therapeutic strategies for AD, although they remain investigational and are not yet an established mainstream treatment. Interestingly, however, ApoE4 is reported to be associated with a reduced risk of retinal degenerative diseases such as glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR). Therefore, should ApoE4 gene editing therapy be approached with caution when AD occurs concurrently with glaucoma, AMD, or DR? In view of these and based on the existing literature, the present study detailed the distinct roles of ApoE4 in AD, glaucoma, AMD, and DR, with a purpose to offer valuable insights into subsequent ApoE4 gene editing therapies. We also summarise the ApoE-targeted therapeutic programmes currently in preclinical and early clinical development, delineate the remaining translational challenges, and discuss how patients with coexisting retinal neurodegenerative disease might be evaluated and monitored.},
}

Humans
*Apolipoprotein E4/genetics
*Gene Editing/methods
*Alzheimer Disease/genetics/therapy/complications
*Genetic Therapy/methods
Animals
*Neurodegenerative Diseases/genetics/therapy/complications
*Retinal Diseases/genetics/therapy/complications
Macular Degeneration/genetics/therapy

@article {pmid42890205,
year = {2026},
author = {Ji, H and Yang, Y and Wu, X and Bao, E},
title = {Safety of lecanemab in real-world patients with Alzheimer's disease: a prospective, observational case series supported by FAERS signal analysis.},
journal = {Frontiers in neuroinformatics},
volume = {20},
number = {},
pages = {1977226},
pmid = {42890205},
issn = {1662-5196},
abstract = {OBJECTIVE: Lecanemab, a humanized immunoglobulin monoclonal antibody, has been approved for the treatment of Alzheimer's disease (AD). Although clinical trials have demonstrated its favorable safety profile, real-world studies are crucial for identifying rare adverse events (AEs) and evaluating post-marketing safety. This study aimed to evaluate the safety of lecanemab by combining a clinical prospective, observational case cohort with data from the FAERS database, thereby providing a robust basis for the identification of potential safety signals.

METHODS: A prospective and observational study was conducted on patients with mild-to-moderate AD receiving lecanemab treatment at a tertiary medical center in China from July 2024 to February 2026. Extracted data included demographic characteristics, time to onset of AEs, and clinical symptoms. Exposure-adjusted incidence rates were calculated per 100 patient-years (PYs). Disproportionality analysis was performed using the US Food and Drug Administration Adverse Event Reporting System (FAERS), and safety signals for AEs observed in the cohort were evaluated utilizing reporting odds ratios (RORs) and proportional reporting ratios (PRRs). Additionally, data from these two real-world sources were compared and cross-validated.

RESULTS: The single-center prospective study enrolled a total of 91 patients. The median duration of lecanemab treatment was 185 days. Thirteen AEs were recorded (56.48/100 PYs), with the most frequent being amyloid-related imaging abnormalities-hemosiderin deposition (ARIA-H; defined as microhemorrhages and hemosiderin deposition) (12.39/100 PYs) and infusion-related reactions (IRRs) (8.85/100 PYs). In the FAERS database, the most frequently reported preferred terms (PTs) included headache, amyloid-related imaging abnormalities-edema/effusion (ARIA-E), ARIA-H, and IRRs. The majority of AEs occurred within the first 1-2 months after initiating lecanemab treatment (n = 393, 45.65%). Furthermore, FAERS analysis revealed a potential safety signal for cerebral infarction. However, this finding must be interpreted cautiously due to the lack of complete data on traditional stroke risk factors and concomitant antithrombotic use in spontaneous reports.

CONCLUSION: In this single-center prospective observational study, lecanemab demonstrated a generally favorable safety profile. Patients with AD aged 65 to 85 years represent a high-risk demographic for AEs. Particular clinical vigilance is required regarding the occurrence of AEs within the first two months of lecanemab initiation. Notably, ARIA (including both ARIA-E and ARIA-H) can occur at any phase during the treatment course.},
}

@article {pmid42890315,
year = {2026},
author = {Cutler, J and Tran, BA and Bullers, K and Fox, C},
title = {Lecanemab-Monoclonal Antibodies for the Treatment of Early Alzheimer's Disease.},
journal = {The Journal of pharmacy technology : jPT : official publication of the Association of Pharmacy Technicians},
volume = {},
number = {},
pages = {87551225261492568},
pmid = {42890315},
issn = {8755-1225},
abstract = {OBJECTIVE: Review the pharmacology, efficacy, and safety of lecanemab, a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody, for the treatment of early Alzheimer's disease (AD).

DATA SOURCES: Comprehensive search of Embase, PubMed, International Pharmaceutical Abstracts, Cochrane CENTRAL, Scopus, Web of Science, and Google Scholar were conducted from inception through December 2025.

Phase I-III clinical trials, systematic reviews, and meta-analyses evaluating lecanemab pharmacology, pharmacokinetics, efficacy, and safety were included. Product labeling was reviewed to supplement clinical data.

DATA SYNTHESIS: In the phase III Clarity AD trial, patients were randomized 1:1 to lecanemab 10 mg/kg every 2 weeks or placebo. The primary endpoint was change from baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) score at 18 months. Lecanemab demonstrated a mean change of 1.21 versus 1.66 with placebo (difference, -0.45; 95% CI, -0.67 to -0.23; P < .001). Secondary endpoint, amyloid burden via positron emission tomography (PET) scans (n = 698) showed -55.48 centiloids with lecanemab versus 3.64 with placebo (difference -59.12 centiloids; 95% CI, -62.64 to -55.6; P < .001). Additional endpoints included changes in ADAS-cog 14, ADCOMS, and ADCS-MCI-ADL scores favoring lecanemab over placebo. Lecanemab was well tolerated; infusion site reactions occurred in 26.4%. Amyloid-related imaging abnormalities (ARIA-E) occurred in 12.6% of participants.

CONCLUSION: Compared to placebo, lecanemab demonstrated statistically significant slowing of cognitive decline on CDR-SB and secondary endpoints, including amyloid burden reduction. However, its clinical benefit must be weighed against ARIA risk and substantial financial burden. Current evidence supports its use in carefully selected patients with early AD under close supervision.},
}

@article {pmid42890532,
year = {2026},
author = {Xi, Q and Wang, S and Shi, Q and Wang, H and Sun, P and Jin, Y and Ma, Y},
title = {Emerging roles of plant-derived extracellular vesicles in the management of dental diseases.},
journal = {Extracellular vesicles and circulating nucleic acids},
volume = {7},
number = {3},
pages = {1600-1624},
pmid = {42890532},
issn = {2767-6641},
abstract = {Dental diseases, including dental caries, pulpitis, and periodontitis, can cause pain and tooth loss, compromising mastication, speech, aesthetics, and quality of life. These diseases have also been associated with systemic disorders, including Alzheimer's disease. Conventional interventions, such as restorative procedures, root canal treatment, and periodontal scaling, have inherent limitations, underscoring the clinical need for novel therapeutic strategies. Plant-derived extracellular vesicles (PDEVs) have recently attracted considerable attention owing to their wide availability, cost-effectiveness, favourable biosafety profile, and capacity to mediate cross-kingdom communication. PDEVs exert diverse biological effects, including antimicrobial, anti-inflammatory, immunomodulatory, and tissue-regenerative activities. For example, ginger-derived PDEVs suppress the growth and virulence of Porphyromonas gingivalis through their lipid and miRNA cargoes, thereby alleviating periodontitis in mice. Given that effective dental therapy requires antimicrobial action, anti-inflammatory effects, immunomodulation, and tissue regeneration, PDEVs are promising therapeutic modalities. This review summarises the isolation, characterisation, composition, and biological functions of PDEVs, and discusses their potential applications in the management of dental diseases.},
}

@article {pmid42891424,
year = {2026},
author = {Tampi, RR and Murphy, K and Golden, J and Schuster, H and Conyers, R},
title = {A review of dextromethorphan and bupropion (Auvelity™) for the treatment of agitation in Alzheimer's disease.},
journal = {Drugs in context},
volume = {15},
number = {},
pages = {},
pmid = {42891424},
issn = {1745-1981},
abstract = {Dextromethorphan hydrobromide and bupropion hydrochloride extended-release tablets (Auvelity[TM]) became the second medication to be approved by the FDA for the treatment of agitation in Alzheimer's disease dementia after brexpiprazole. It also became the first non-antipsychotic medication to be approved for this specific indication. In this Editorial, the available data regarding the efficacy and adverse effects of this medication in the treatment of agitation in Alzheimer's disease dementia are reviewed.},
}

@article {pmid42884579,
year = {2026},
author = {Intharuksa, A and Prasansuklab, A and Techarang, T and Chaikhong, K and Arunotayanun, W and Jenraumjit, R},
title = {The Role of Herbal Medicines in Cognitive Impairment: A Narrative Review of Neuroprotective Mechanisms and Therapeutic Perspectives.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
pmid = {42884579},
issn = {2072-6643},
mesh = {Humans ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; *Cognitive Dysfunction/drug therapy ; *Phytotherapy/methods ; *Plant Preparations/therapeutic use/pharmacology ; Plant Extracts/pharmacology/therapeutic use ; Plants, Medicinal ; Cognition/drug effects ; },
abstract = {Cognitive impairment encompasses a clinical spectrum ranging from mild cognitive impairment to dementia, particularly Alzheimer's disease (AD), and involves interconnected pathological processes including cholinergic dysfunction, oxidative stress, neuroinflammation, mitochondrial impairment, amyloid-β accumulation, tau hyperphosphorylation, and synaptic loss. Herbal medicines have attracted increasing attention because their complex phytochemical composition may provide multi-target neuroprotective effects. This narrative review aimed to summarize current preclinical and clinical evidence on herbal medicines and traditional herbal formulations for cognitive impairment, with emphasis on their mechanisms, therapeutic potential, safety, and translational limitations. Relevant evidence from in vitro studies, animal models, randomized clinical trials, systematic reviews, and meta-analyses was narratively synthesized. The review considered single herbal medicines, standardized extracts, isolated phytochemicals, and traditional multi-herbal formulations, together with their reported cognitive outcomes and molecular targets. Preclinical studies suggest that selected herbal preparations may modulate pathways implicated in cognitive impairment through acetylcholinesterase and butyrylcholinesterase inhibition, antioxidant and mitochondrial protection, suppression of neuroinflammatory signaling, modulation of amyloidogenic and tau-related pathways, and enhancement of BDNF/TrkB- and CREB-associated neuroplasticit; however, clinical evidence remains limited and heterogeneous. Clinical studies of Bacopa monnieri, Panax ginseng, Crocus sativus, and several traditional Chinese, Korean, and Persian formulations have reported improvements in memory and global cognitive measures, including MMSE, MoCA, and ADAS-cog scores. However, evidence remains constrained by heterogeneity of products, small sample sizes, short treatment periods, inconsistent outcome measures, limited biomarker integration, and incomplete long-term safety assessment. Herbal medicines show potential as preventive, complementary, or adjunctive approaches for cognitive impairment, but they cannot yet be considered established replacements for conventional therapy. Standardized products, rigorous pharmacokinetic and toxicological evaluation, disease-relevant models, and adequately powered multicenter trials are required to support evidence-based clinical application.},
}

Humans
*Neuroprotective Agents/therapeutic use/pharmacology
Animals
*Cognitive Dysfunction/drug therapy
*Phytotherapy/methods
*Plant Preparations/therapeutic use/pharmacology
Plant Extracts/pharmacology/therapeutic use
Plants, Medicinal
Cognition/drug effects

@article {pmid42884722,
year = {2026},
author = {Dube, K and Stoinescu, A and Sadler, J and Truong, M and Malakoti-Negad, N and Chaudhry, M and Talukdar, R and Cohen, J and Pandey, S},
title = {Multidimensional Neuroprotective Effects of Combined Ubisol-Q10 and Ashwagandha (Withania somnifera) in Male and Female 5XFAD Mice.},
journal = {Nutrients},
volume = {18},
number = {19},
pages = {},
pmid = {42884722},
issn = {2072-6643},
support = {809194//This work was supported through donations from the Szecsei and Dhar families (grant # 809194)./ ; },
mesh = {Animals ; Male ; Female ; *Neuroprotective Agents/pharmacology ; *Withania/chemistry ; *Alzheimer Disease/drug therapy/pathology ; *Plant Extracts/pharmacology ; Mice ; Disease Models, Animal ; Autophagy/drug effects ; Mice, Transgenic ; Brain/drug effects/pathology ; },
abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by interconnected pathological processes including mitochondrial dysfunction, oxidative stress, impaired autophagic processes, neuroinflammation, neuronal degeneration, and progressive functional decline. Natural health products (NHPs), coenzyme-Q10 (CoQ10) and Ashwagandha (Withania somnifera) (ASH), have been previously reported to possess antioxidant, anti-inflammatory, mitochondrial-supportive, neuroprotective, and neurotrophic properties. This work investigates the neuroprotective effects of a bioavailability-enhanced formulation, Ubisol-Q10 (UQ), and ethanolic ASH extract, combined as a "Tonic," across multiple domains of AD pathology.

METHODS: The effects of long-term administration were evaluated in male and female 5XFAD mice from 2.5 to 11 months of age. Longitudinal magnetic resonance imaging assessed hippocampal and white matter volumes, a frailty index assessed physiological resilience, Novel Object and Novel Location Recognition testing assessed spatial and non-spatial memory, while post-mortem Nissl, Golgi-Cox, and immunofluorescence evaluated cellular density, dendritic morphology, amyloid pathology, neuroinflammation, autophagy-associated signaling, and astrocytic activity.

RESULTS: Across these measures, Tonic treatment preserved brain volumes, reduced amyloid pathology and inflammation, and modulated autophagy-associated pathways. Treatment also preserved dendritic architecture, frailty progression, and novelty-recognition behavior. Females demonstrated particularly pronounced preservation of white matter structure and increased dendritic density, whereas males showed strong modulation of inflammatory and autophagy-associated markers. Astrocytic immunoreactivity also demonstrated sex- and region-specific patterns, suggesting that glial responses may contribute differently to structural preservation in males and females.

CONCLUSIONS: Together, these findings support that UQ + ASH may provide diverse protection against AD neurodegeneration. The observed sex-specific responses emphasize the importance of incorporating sex into preclinical evaluation of novel interventions for neurodegenerative diseases.},
}

Animals
Male
Female
*Neuroprotective Agents/pharmacology
*Withania/chemistry
*Alzheimer Disease/drug therapy/pathology
*Plant Extracts/pharmacology
Mice
Disease Models, Animal
Autophagy/drug effects
Mice, Transgenic
Brain/drug effects/pathology

@article {pmid42885186,
year = {2026},
author = {Joseph, JM and Rachel, J and Han, G and Smith, ML},
title = {Comparing Health Care Utilization Between Medicare Advantage and Traditional Medicare by Dementia Status: A Propensity-Weighted Analysis.},
journal = {Health services research},
volume = {61},
number = {5},
pages = {e70174},
pmid = {42885186},
issn = {1475-6773},
mesh = {Humans ; United States ; Female ; Aged ; *Medicare Part C/statistics & numerical data ; Male ; Cross-Sectional Studies ; *Patient Acceptance of Health Care/statistics & numerical data ; *Dementia/epidemiology/therapy ; *Medicare/statistics & numerical data ; Aged, 80 and over ; Propensity Score ; Alzheimer Disease ; },
abstract = {OBJECTIVE: To compare health care utilization between Medicare Advantage (MA) and Traditional Medicare (TM) beneficiaries, stratified by Alzheimer's disease and related dementias (ADRD) status.

STUDY SETTING AND DESIGN: Repeated cross-sectional observational analysis of community-dwelling Medicare beneficiaries aged ≥ 65 years continuously enrolled in MA or TM. Eight self- or proxy-reported binary utilization outcomes over a 12-month reference period were estimated by survey-weighted linear probability models stratified by ADRD status.

Secondary analysis of pooled 2018-2022 Medicare Current Beneficiary Survey (MCBS) public use files (N = 43,995: 974 TM and 954 MA with ADRD; 23,050 TM and 19,017 MA without ADRD), excluding beneficiaries entitled through disability or end-stage renal disease and records with missing covariates. Dual-eligible beneficiaries were retained and dual eligibility included as a covariate. Stabilized inverse probability of treatment weights multiplied by MCBS full-sample weights addressed non-random MA enrollment.

PRINCIPAL FINDINGS: Among beneficiaries with ADRD, seven of eight adjusted MA - TM differences were not statistically significant. Specialist visits were more common among MA beneficiaries with ADRD (5.2 percentage points; 95% CI, -0.1 to 10.2). Among beneficiaries without ADRD, MA was associated with lower outpatient hospital visits (-2.6; -3.7 to -1.6) and lower reported need for home health visits (-0.9; -1.5 to -0.3). Effect modification by ADRD status was significant only for specialist visits (interaction 6.3 percentage points; p = 0.004).

CONCLUSIONS: Adjusted health care utilization was broadly comparable between MA and TM for beneficiaries with ADRD, with the exception of higher specialist use in MA. Among beneficiaries without ADRD, MA was associated with lower outpatient hospital use. Plan-type differences were smaller and fewer for beneficiaries with ADRD.},
}

Humans
United States
Female
Aged
*Medicare Part C/statistics & numerical data
Male
Cross-Sectional Studies
*Patient Acceptance of Health Care/statistics & numerical data
*Dementia/epidemiology/therapy
*Medicare/statistics & numerical data
Aged, 80 and over
Propensity Score
Alzheimer Disease

@article {pmid42885191,
year = {2026},
author = {Lee, S and Kim, K and Kim, H and Oh, MS and Yoon, K and Kwak, S and Kim, J and Lee, GH and Kim, Y and Kim, J},
title = {Focused Ultrasound as a Plasma Protein Binding-targeted Strategy to Enhance Brain Uptake of Donepezil.},
journal = {Experimental neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.5607/en26028},
pmid = {42885191},
issn = {1226-2560},
abstract = {Donepezil, a reversible acetylcholinesterase inhibitor, is widely used for the symptomatic treatment of Alzheimer's disease (AD). Although higherdose donepezil has been shown to provide additional clinical benefit, dose escalation is often limited by cholinergic adverse effects. Given that approximately 96% of circulating donepezil is bound to plasma proteins, especially albumin, we hypothesized that increasing its unbound fraction from albumin may improve brain delivery without increasing the administered dose. To achieve this goal, herein we examined whether the donepezil-albumin complex can be dissociated by low-intensity focused ultrasound (FUS) in vitro. Then brain uptake of donepezil was evaluated in mice receiving intravenous donepezil followed by targeted brain FUS stimulation. As a result, FUS significantly increased unbound fraction of donepezil at the targeted region in vitro, resulting in a 41.1% increase of donepezil diffusion into dialysis cassettes compared with non-sonicated controls. In mice receiving intravenous donepezil, targeted brain FUS stimulation increased brain donepezil concentrations by 52.7% at 15-min post-administration time. These findings suggest that low-intensity FUS enhances brain uptake of donepezil, potentially through modulation of donepezil-albumin binding, and support further investigation of plasma protein binding-targeted brain drug delivery.},
}

@article {pmid42856725,
year = {2026},
author = {Razavi, A and Tucker, NR and Ghosh, AJ and Faraone, SV and Glatt, SJ and Hess, JL},
title = {Predicting Rates of Cognitive Decline in Older Adults with Brain- and Cardiac-Imputed Transcripts.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42856725},
abstract = {Severe cognitive decline due to dementia is an important clinical indicator signaling neurodegeneration. Predicting cognitive decline rates can be useful in establishing prognosis and modifying treatment regimens. The rate of decline is highly variable across patients with dementia and may be determined by an interplay of many factors. This variability poses challenges to existing tools for predicting disease progression. Changes in heart and brain tissue have been associated with cognitive decline, yet tissue-specific molecular data are difficult to obtain. In this study, we sought to estimate cognitive decline-related transcripts in the brain and heart of people actively living with and without dementia. We reconstructed transcriptomic profiles in brain and heart with the transcriptome-imputation algorithms BrainGENIE and HeartGENIE, and identified several hundreds of transcripts associated with cognitive decline over a two-year assessment window, with the cerebellar hemisphere, left ventricle of the heart, and atrial appendage showing the largest number of cognitive-related transcripts. Pathway analysis revealed an enrichment among cognition-related transcripts of gene sets involved in synaptic, proteostasis/autophagy, immunologic, and mitochondrial respiratory chain functioning. Hundreds of perturbagens show significant concordance with cognitive decline-related transcriptomic signatures in brain and heart, pointing to potentially druggable targets. Top brain- and heart-specific cognition-associated transcripts were incorporated into LASSO regression models predicting future cognitive decline and were compared to two models, one utilizing age, sex and educational attainment, and a hybrid model incorporating both data types. Our models were able to achieve statistically significant correlations in the test set, yet had weak overall. Together, these findings demonstrate that brain and heart transcriptomes capture distinct aspects of biology related to cognitive decline, providing more nuanced insights into normal and aberrant brain aging that may inform drug-repurposing and risk-prediction efforts.},
}

@article {pmid42884062,
year = {2026},
author = {Kuikel, K and McEwen, A and Mathiske, TJ and Wojtaszak, L and John, JAS and Delbaz, A},
title = {Combined Effects of Chlamydia pneumoniae Infection and Hypoxia on Glial Metabolism and Alzheimer's Disease-Related Pathways.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198820},
pmid = {42884062},
issn = {1422-0067},
support = {//Clem Jones Foundation/ ; //Goda Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology/pathology ; *Chlamydophila pneumoniae ; Amyloid beta-Peptides/metabolism ; *Neuroglia/metabolism ; Astrocytes/metabolism/microbiology ; Cell Hypoxia ; *Hypoxia/metabolism ; Microglia/metabolism/microbiology ; Cell Line ; Proteomics/methods ; *Chlamydophila Infections/metabolism ; *Chlamydia Infections/metabolism ; },
abstract = {Alzheimer's disease involves complex interactions among neuroinflammation and metabolic dysfunction. Emerging evidence implicates microbial pathogens and hypoxia as converging stressors, yet their combined impact on glial function remains poorly understood. Human astrocyte and microglial cell lines were exposed to four experimental conditions: (i) normoxic control, (ii) Chlamydia pneumoniae infection under normoxia, (iii) hypoxia control and (iv) Chlamydia pneumoniae infection under hypoxic conditions. Hypoxia was induced at 3% oxygen for 72 h. Cellular responses were assessed using NanoString nCounter transcriptomics using the Alzheimer's Disease and Metabolic Pathways panels, Tandem Mass Tag proteomics, MTT reduction, glucose uptake, intracellular ATP quantification and amyloid beta quantification by ELISA. Combined exposure to infection and hypoxia was associated with cell-type-specific alterations in glial metabolic and transcriptional responses. Factorial transcriptomic analysis identified significant infection × oxygen interactions across both NanoString panels and glial cell types. Proteomic responses differed according to cell type and oxygen availability. Aβ40 and Aβ42 measurements demonstrated treatment-associated alterations in the extracellular Aβ peptide profile, including increased Aβ42/Aβ40 ratios following infection. Together, these findings demonstrate distinct and interacting effects of infection and hypoxia on glial metabolic and molecular responses and identify Alzheimer's disease-related cellular changes warranting further investigation in physiologically relevant models.},
}

Humans
*Alzheimer Disease/metabolism/microbiology/pathology
*Chlamydophila pneumoniae
Amyloid beta-Peptides/metabolism
*Neuroglia/metabolism
Astrocytes/metabolism/microbiology
Cell Hypoxia
*Hypoxia/metabolism
Microglia/metabolism/microbiology
Cell Line
Proteomics/methods
*Chlamydophila Infections/metabolism
*Chlamydia Infections/metabolism

@article {pmid42879726,
year = {2026},
author = {Reynolds, EL and Elafros, MA and Muthukumar, L and Shippey, E and Budhu, JA and Terman, SW and Burke, JF and Callaghan, BC},
title = {Predictors of Antiamyloid Medication Utilization and Adherence Among People With Alzheimer Disease and Mild Cognitive Impairment.},
journal = {Neurology},
volume = {107},
number = {9},
pages = {e218594},
doi = {10.1212/WNL.0000000000218594},
pmid = {42879726},
issn = {1526-632X},
mesh = {Humans ; Female ; *Alzheimer Disease/drug therapy ; Male ; Aged ; *Cognitive Dysfunction/drug therapy ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized/therapeutic use ; *Drug Monitoring ; *Medication Adherence ; },
abstract = {BACKGROUND AND OBJECTIVES: From 2021 to 2024, 3 amyloid monoclonal antibody medications (aducanumab, lecanemab, and donanemab) were approved by the US Food and Drug Administration for treatment of mild cognitive impairment (MCI) and mild dementia due to Alzheimer disease (AD). We determined the demographics and social drivers of health associated with utilization and initial adherence of these medications.

METHODS: We used the Vizient database to identify patients with MCI or dementia using an ICD-10 coding definition. Propensity score matching was used to match patients who received an antiamyloid medication to those who did not, based on date of MCI/dementia diagnosis and follow-up. Social drivers of health were assessed using the Vizient Vulnerability Index (VVI), a neighborhood-level measure of socioeconomic vulnerability. Logistic regression determined associations between demographics, Elixhauser comorbidity, and VVI, with utilization of antiamyloid medications. Poisson regression determined associations between demographic, Elixhauser comorbidity, and VVI and initial adherence (measured as days supplied) of antiamyloid medications.

RESULTS: We identified 1,198,362 participants with MCI/dementia, of whom 2,427 (0.2%) were prescribed an antiamyloid medication. Of those prescribed an antiamyloid medication, 1,696 (69.9%) were matched to participants with MCI/dementia that were not prescribed antiamyloid medications (mean age 75.5 [SD 9.5], 56.1% female, 80.1% non-Hispanic White). We found that higher age (odds ratio [OR] 0.93, 95% CI 0.92-0.94), higher Elixhauser comorbidity index (OR 0.56, 95% CI 0.52-0.59), being non-Hispanic Black (OR 0.14, 95% CI 0.09-0.23), and being Hispanic (OR 0.21, 95% CI 0.13-0.36) associated with lower odds of receiving an antiamyloid medication. Furthermore, having greater VVI was associated with lower odds of receiving an antiamyloid medication. By contrast, only higher Elixhauser comorbidity score was associated with lower initial medication adherence (rate ratio 0.94, 95% CI 0.93-0.96), but not age, sex, race/ethnicity, and overall vulnerability.

DISCUSSION: We found that younger, non-Hispanic White patients, with fewer comorbidities, and lower vulnerability, were more likely to receive antiamyloid medications. By contrast, among patients receiving an antiamyloid medication, only higher comorbidity score associated with lower initial medication adherence. These findings indicate a potential disparity in medication access for US patients with MCI/dementia that could become problematic barriers to care as medications for dementia continue to evolve.},
}

Humans
Female
*Alzheimer Disease/drug therapy
Male
Aged
*Cognitive Dysfunction/drug therapy
Aged, 80 and over
Antibodies, Monoclonal, Humanized/therapeutic use
*Drug Monitoring
*Medication Adherence

@article {pmid42880054,
year = {2026},
author = {Benussi, A and Agosta, F and Agnello, L and Alfano, AR and Altini, M and Antico, A and Basilico, S and Bellelli, G and Bonanni, L and Bottini, G and Bozzali, M and Brignoli, O and Bruno, G and Cagnin, A and Calloni, SF and Cappa, SF and Caraci, F and Cecchin, D and Ciaccio, M and Cocozza, S and Cosottini, M and De Leo, D and Falini, A and Gaetani, L and Gandolfo, N and Gotta, F and Lodi, R and Logroscino, G and Marcello, E and Marra, C and Marrocco, W and Morbelli, S and Mecocci, P and Mossello, E and Palleschi, L and Palumbo, P and Pantoni, L and Parnetti, L and Roccatagliata, L and Sorbi, S and Spadin, P and Splendiani, A and Tessitore, A and Ungar, A and Zappalà, G and Padovani, A},
title = {Updated Italian intersocietal recommendations for the appropriate use of anti-amyloid monoclonal antibodies in Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {10},
pages = {100685},
doi = {10.1016/j.tjpad.2026.100685},
pmid = {42880054},
issn = {2426-0266},
abstract = {With the European authorisation of lecanemab and donanemab, Italy is entering the era of disease-modifying therapy for early symptomatic Alzheimer's disease. The Italian Expert Panel on Alzheimer (EPA), which convened 21 scientific societies and patient associations and published a first set of intersocietal recommendations in 2025, was reconvened in Rome on 24 January 2026 (EPA2) to address the operational gaps that had emerged during the implementation of that document. A modified Delphi process was adopted to formalise consensus on the most controversial points raised during the meeting. Thirty-six declarative statements covering five domains, namely the tiered organisation of the Centres for Cognitive Disorders and Dementia (CDCD), clinical staging and treatment monitoring, eligibility considerations in mild cognitive impairment and atypical phenotypes, composition of the multidisciplinary team, and magnetic resonance imaging thresholds, ARIA monitoring and biomarker pathway, were submitted to a multidisciplinary panel of experts. Strong agreement was reached on the large majority of statements, providing quantitative endorsement for a competence-based reorganisation of the CDCD network, the harmonised use of the Clinical Dementia Rating, an explicit composition of the multidisciplinary team, trial-aligned magnetic resonance imaging eligibility criteria with a move towards risk-adapted ARIA monitoring, and a stepwise biomarker pathway integrating plasma assays, cerebrospinal fluid analysis on automated platforms and amyloid positron emission tomography. The document provides Italian regional and national health systems, prescribing centres and reimbursing authorities with a quantitative blueprint for the appropriate, equitable and sustainable use of anti-amyloid monoclonal antibodies in clinical practice.},
}

@article {pmid42880601,
year = {2026},
author = {Barberà-Parada, S and Biosca-Brull, J and Gabaldón-Díaz, R and Rodulfo-Cárdenas, R and Guardia-Escoté, L and Blanco, J and Cabré, M and Colomina, MT},
title = {Sex-divergent vulnerability to chronic peripheral LPS challenge in aged ApoE4 mice: Male systemic fragility versus female central neuroinflammation.},
journal = {Behavioural brain research},
volume = {517},
number = {},
pages = {116524},
doi = {10.1016/j.bbr.2026.116524},
pmid = {42880601},
issn = {1872-7549},
abstract = {Inflammageing links chronic inflammation to biological aging, contributing to senescence and multimorbidity common in the elderly. In neurodegenerative diseases, such as Alzheimer's disease, inflammatory processes play a causal role in accelerating neurodegeneration. Interestingly, apolipoprotein E (APOE), particularly the APOEε4 allele, is a major genetic risk factor for neurodegeneration, acting as a key immunomodulator with sex differences. This is especially relevant given the lack of clear prevention strategies for APOEε4 carriers. Therefore, this study characterized the sex-specific neuroinflammatory and cognitive vulnerability of APOE4 genotype under a chronic lipopolysaccharide (LPS) challenge in senescence-transition stage. Male and female homozygous apoE4 mice (15-16 months old) were administered intraperitoneal doses of 0 or 0.25 mg/kg LPS three times per week for a total of 17 doses. Body weight was monitored, and behavioural assessments were conducted from the 12th injection until the 17th. Serum and tissues were collected to assess hippocampal, cortical and systemic markers of inflammation, antioxidant-related genes, genes implied in myelin dynamics, and neurotrophin-related transcripts. Findings revealed basal sex-dependent divergent phenotypes with specific responses under LPS challenge. Under LPS treatment, males exhibited higher systemic fragility, with significantly increased mortality, which may have conditioned cognitive outcomes. Females showed greater central alterations related to neuroinflammation along with altered expression of myelin-related transcripts. However, the results suggest a stablished tolerance to LPS. These results highlight how chronic systemic inflammation during ageing in an APOE4 genotype background shapes sex-divergent pathological trajectories, underscoring the need to address sex-specific therapeutic strategies.},
}

@article {pmid42882500,
year = {2026},
author = {Alam, JJ and Germann, UA and Maruff, P},
title = {Targeting Pro-Inflammatory Interleukin-1 Beta Signaling to Modulate Neuroinflammatory Processes Associated with Cognitive Decline in Dementia with Lewy Bodies.},
journal = {Cells},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/cells15191803},
pmid = {42882500},
issn = {2073-4409},
support = {//CervoMed Inc/ ; #R01AG080536/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Interleukin-1beta/metabolism ; *Lewy Body Disease/drug therapy/complications/metabolism ; *Signal Transduction/drug effects ; *Neuroinflammatory Diseases/metabolism/drug therapy ; *Cognitive Dysfunction/drug therapy/complications/metabolism ; Amyloid beta-Peptides ; Female ; Alzheimer Disease/drug therapy ; Male ; Interleukin-6/metabolism ; },
abstract = {Interleukin-1 beta (IL-1β) is implicated as a molecular driver of cognitive decline in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), potentially through activation of pro-inflammatory pathways within the neuron that impair synaptic function. Because pro-inflammatory IL-1β signaling depends on p38α kinase, the oral brain-penetrant p38α inhibitor neflamapimod has the potential to reverse synaptic dysfunction and treat cognitive decline in these contexts. Neflamapimod has also shown positive effects in animal models and in clinical studies in AD and DLB. Herein we evaluated neflamapimod effects on pro-inflammatory IL-1β signaling in vitro and in patients with AD or DLB. In human PBMCs, neflamapimod inhibited IL-1β-induced IL-6 and IL-8 production with EC50 values of 6.3 ± 1.3 nM and 7.1 ± 3.2 nM, respectively. In AD, six weeks of neflamapimod 40 mg BID treatment reduced CSF levels of IL-6 and IL-8, with maximal effects at trough drug concentration ≥4 ng/mL (9 nM). In DLB, neflamapimod 40 mg TID increased the plasma Aβ42/40 ratio and reduced plasma GFAP levels, treatment effects consistent with reduced pro-inflammatory IL-1β signaling. Collectively, these results support the hypothesis that inhibition of p38α-dependent IL-1β signaling may beneficially modulate neuroinflammatory processes that otherwise are associated with cognitive decline in DLB, and potentially in AD.},
}

Humans
*Interleukin-1beta/metabolism
*Lewy Body Disease/drug therapy/complications/metabolism
*Signal Transduction/drug effects
*Neuroinflammatory Diseases/metabolism/drug therapy
*Cognitive Dysfunction/drug therapy/complications/metabolism
Amyloid beta-Peptides
Female
Alzheimer Disease/drug therapy
Male
Interleukin-6/metabolism

@article {pmid42883332,
year = {2026},
author = {Işık, M and Syla, GH and Karakaya, A and Çevik, UA and Daoud, NE and Fırat, M and Öğünç Keçeci, Y and Özkay, Y and Kaplancıklı, ZA and Beydemir, Ş},
title = {Design and Synthesis of New Thiazole Derivatives for Alzheimer's Disease Therapy as a Potential Cholinesterase Inhibitor; Toxicity Prediction and Molecular Docking Studies and Biological Evaluation.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {19},
pages = {},
doi = {10.3390/molecules31193568},
pmid = {42883332},
issn = {1420-3049},
support = {//Anadolu University/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology ; Molecular Docking Simulation ; *Thiazoles/chemistry/chemical synthesis/pharmacology ; *Alzheimer Disease/drug therapy/enzymology ; Humans ; Butyrylcholinesterase/chemistry/metabolism ; Acetylcholinesterase/chemistry/metabolism ; *Drug Design ; Structure-Activity Relationship ; Molecular Structure ; Animals ; },
abstract = {In this study, thiazole derivatives 13-23 were synthesized as novel cholinesterase inhibitors. Their structures were elucidated using [1]H-NMR, [13]C-NMR, and elemental analysis techniques. The binding positions and efficiencies of the designed compounds on the enzyme were investigated through molecular docking studies, and the properties of ADMET were examined using computational methods. Cytotoxicity analyses of the synthesized compounds were performed to screen their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro. It has been determined that these compounds do not exhibit a significant cytotoxic effect on healthy endothelial cells. Although the compounds showed lower efficacy in AChE inhibition compared to the reference compound tacrine (IC50: 0.136 μM; KI: 0.46 ± 0.01 nM), they exhibited moderate inhibitory effects. Among these, compounds 16 and 23 were found to be the most potent AChE inhibitors, with IC50 values of 36.47 µM and 34.65 µM, and KI values of 22.20 ± 1.23 and 21.10 ± 1.58 µM, respectively, while compounds 15 and 20 were found to be the most potent BChE inhibitors, with IC50 values of 17.76 µM and 16.90 µM, and KI values of 14.10 ± 0.58 and 13.40 ± 0.48 µM, respectively, on other cholinesterases. These tested compounds can be considered potential candidates for further research in the treatment of Alzheimer's disease (AD).},
}

*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology
Molecular Docking Simulation
*Thiazoles/chemistry/chemical synthesis/pharmacology
*Alzheimer Disease/drug therapy/enzymology
Humans
Butyrylcholinesterase/chemistry/metabolism
Acetylcholinesterase/chemistry/metabolism
*Drug Design
Structure-Activity Relationship
Molecular Structure
Animals

@article {pmid42883911,
year = {2026},
author = {Rojas-Sánchez, I and Cortes-Flores, E and Camacho-Concha, N and Almazán, JL and Ramírez-Lugo, L and Crivelli-Galindo, E and Ramirez-Serrano, CE and Pedraza-Alva, G and Pérez-Martínez, L},
title = {Therapeutic Administration of Malva parviflora Hydroalcoholic Extract Restores Cognitive Function Consistent with a Resilient Phenotype in Female 5XFAD.},
journal = {International journal of molecular sciences},
volume = {27},
number = {19},
pages = {},
doi = {10.3390/ijms27198665},
pmid = {42883911},
issn = {1422-0067},
support = {PAPIIT IN217822//Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (UNAM)/ ; PAPIIT IN222925//Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (UNAM)/ ; PAPIIT IN216922//Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (UNAM)/ ; CBF2023-2024-878//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; IFC 2016-2282//Consejo Nacional de Humanidades, Ciencias y Tecnologías/ ; },
mesh = {Animals ; Female ; *Plant Extracts/pharmacology/chemistry/administration & dosage ; *Cognition/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Hippocampus/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; *Malva/chemistry ; Mice, Transgenic ; Long-Term Potentiation/drug effects ; Phenotype ; Disease Models, Animal ; Glial Fibrillary Acidic Protein/metabolism ; Neuronal Plasticity/drug effects ; },
abstract = {The remarkable increase in human life expectancy has been accompanied by a rising global incidence of neurodegenerative disorders, particularly Alzheimer's disease. This condition is characterized by progressive accumulation of soluble and insoluble amyloid-beta peptides, neuroinflammation, and synaptic dysfunction in the hippocampus, leading to impaired higher-order cognition. Epidemiological evidence indicates that women are disproportionately affected; however, female-specific pathology remains understudied. Here, we evaluated the therapeutic potential of a hydroalcoholic extract of Malva parviflora in female 5XFAD mice following prolonged intragastric administration initiated after disease establishment. Long-term treatment shifted cognitive performance toward a phenotype comparable to wild-type littermates, an improvement associated with reduced soluble amyloid-beta levels in the hippocampus and peripheral circulation, and significant attenuation of reactive astrogliosis as evidenced by reduced hippocampal glial fibrillary acidic protein levels. Because reactive astrocytes impair synaptic activity and metabolic homeostasis during disease progression, we examined the direct effects of Malva parviflora on synaptic plasticity ex vivo. Incubation of hippocampal synaptosomes from adult female 5XFAD mice with the extract restored chemically induced long-term potentiation. These findings demonstrate that Malva parviflora attenuates key pathological hallmarks of Alzheimer's disease and promotes cognitive recovery, supporting its potential as a plant-derived therapeutic candidate, particularly in females most affected by Alzheimer's disease. Future studies including both sexes under a therapeutic paradigm are needed to determine the generalizability of these findings.},
}

Animals
Female
*Plant Extracts/pharmacology/chemistry/administration & dosage
*Cognition/drug effects
*Alzheimer Disease/drug therapy/metabolism
Mice
Hippocampus/drug effects/metabolism
Amyloid beta-Peptides/metabolism
*Malva/chemistry
Mice, Transgenic
Long-Term Potentiation/drug effects
Phenotype
Disease Models, Animal
Glial Fibrillary Acidic Protein/metabolism
Neuronal Plasticity/drug effects

@article {pmid42877349,
year = {2026},
author = {Yuan, X and Tang, Q and Wang, T},
title = {Screening of herbs for vascular dementia: Through the combination of reverse network pharmacology and traditional Chinese medicine enrichment analysis.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261466619},
pmid = {42877349},
issn = {2542-4823},
abstract = {BACKGROUND: Vascular dementia (VaD) represents the second most prevalent form of cognitive impairment following Alzheimer's disease. Its pathological mechanisms encompass a complex interplay of cerebral ischemia, inflammatory responses, oxidative stress, and neuronal apoptosis. Current clinical interventions predominantly target cerebral circulation enhancement and neuroprotection; however, these approaches exhibit limitations in efficacy, single-target specificity, and significant adverse effects. Traditional Chinese medicine (TCM) offers a novel therapeutic paradigm for complex diseases owing to its multi-target synergistic effects, low toxicity profile, and integrated preventive and therapeutic benefits.

OBJECTIVE: This study aims to identify the potentially effective active components in TCM targeting VaD, and to elucidate the multi-target regulatory mechanisms.

METHODS: This study employed a "disease-gene-drug" reverse screening model, integrating bioinformatics and network pharmacology, to systematically identify potential TCM candidates for VaD treatment and elucidate their multi-target regulatory mechanisms.

RESULTS: A total of eight TCM agents with potential VaD therapeutic efficacy (including Niuxi, Pueraria lobata, and Citrus aurantium) were identified, alongside nine active compounds and nine therapeutic targets. Notably, Gehua and Zhike were reported for the first time to exhibit potential VaD therapeutic effects. Furthermore, molecular docking technology was utilized to investigate the binding affinity and interaction modes of these nine active compounds with key targets.

CONCLUSIONS: To our knowledge, this study is among the first to apply reverse network pharmacology combined with TCM enrichment specifically to VaD.},
}

@article {pmid42877369,
year = {2026},
author = {Shrestha, N and Chiang, C and Wei, YJ},
title = {Central nervous system-active medication polypharmacy and risk for nursing home admission among adults with early-onset dementia: A retrospective cohort study.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261472831},
pmid = {42877369},
issn = {2542-4823},
abstract = {BACKGROUND: While central nervous system (CNS)-active medication polypharmacy is prevalent among adults with early-onset dementia (EOD), its impact on nursing home (NH) admission is unclear.

OBJECTIVE: To examine whether CNS-active medication polypharmacy is associated with risk for NH admission among patients with EOD.

METHODS: A retrospective cohort study using 2012-2021 MarketScan Databases was conducted with adults aged 30 to 64 years diagnosed with Alzheimer's disease and related dementias (ADRD). CNS-active medication polypharmacy was assessed during a fixed 6-month period after an indexed ADRD diagnosis and defined as concurrent use of ≥3 CNS-active medications on the American Geriatrics Society Beers Criteria list that overlapped for ≥30 consecutive days. Cox hazards models were used to estimate the hazard ratio (HR) of NH admission between patients with versus without CNS-active medication polypharmacy, with adjustment for baseline covariates via inverse probability of treatment weighting.

RESULTS: Of the 18,029 patients with EOD identified, those with CNS-active medication polypharmacy (versus those without) had an increased risk of NH admission (HR, 1.34 [95% CI, 1.16-1.56]). The risk was pronounced in patients aged >50 years, male patients, patients with a diagnosis of Alzheimer's disease or senile dementia, and patients having baseline use of anti-dementia medications.

CONCLUSIONS: In this commercially insured population of adults with EOD, receipt of CNS-active medication polypharmacy was associated with risk for NH admission. The finding, however, should be interpreted with caution, as it may reflect differences in the underlying disease severity and clinical indications treated by the studied CNS-active medications.},
}

@article {pmid42877383,
year = {2026},
author = {Ferrer, A and Moon, J},
title = {Lecanemab real-world treatment outcomes from cohort study in early Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261470042},
pmid = {42877383},
issn = {2542-4823},
abstract = {Lecanemab has demonstrated amyloid reduction and slowed clinical decline in early Alzheimer's disease trials. Herein, we report retrospective case series results on lecanemab treatment in our clinic. Overall, 61 individuals were included. For the 33 patients with Kokmen Mental Status Exam baseline and post-baseline scores, 67% had either improved or stable scores. Nine incident amyloid-related imaging abnormalities were observed with all but one patient continuing treatment. Six patients were safely transitioned from aducanumab to lecanemab treatment upon market withdrawal of aducanumab. In a real-world clinical practice setting, the lecanemab effectiveness and safety profile were similar to that observed in clinical studies.},
}

@article {pmid42877391,
year = {2026},
author = {Granadillo, E and Peterson, A and Bloyer, E and Hancock, LM and Shah-Basak, P and Kraegel, P and Schold, S and Okonkwo, O and Nair, VA and Prabhakaran, V and Ikonomidou, C},
title = {Multifield extended high-definition transcranial direct current stimulation in mild cognitive impairment: A proof-of-concept study on cognition and brain network connectivity.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261449802},
pmid = {42877391},
issn = {2542-4823},
abstract = {BACKGROUND: Treatment of mild cognitive impairment (MCI) could delay the progression of cognitive decline. Noninvasive neuromodulation might restore brain plasticity and lead to clinically meaningful cognitive improvements.

OBJECTIVE: To investigate feasibility and tolerability of a multi-field (four regions) extended (80-min-long) intervention using high-definition transcranial direct current stimulation (HD-tDCS) combined with computerized cognitive training (CCT) in participants with MCI and to explore its effects on cognition and brain functional connectivity.

METHODS: Double-blinded, randomized proof-of-concept trial of daily sham HD-tDCS + CCT (n = 4) or anodal HD-tDCS + CCT (n = 4) for 15 sessions over 3 months. Four cortical regions were targeted using neuronavigation, including putative frontal coordinates of cognitive reserve and lateral parietal coordinates hypothesized to have robust hippocampal connectivity. Neurocognitive outcomes were assessed at 3 and 6 months and resting-state functional connectivity changes were evaluated at 3 months. Statistical analysis included independent sample t-tests, Wilcoxon rank-sum tests, and Bonferroni correction for multiple comparisons.

RESULTS: Eleven subjects were eligible and interviewed, and 8 consented (73% consent rate). All 8 completed the trial with only minor adverse events (100% completion rate). Blinding was successful. A large but non-significant increase in Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite scores at 6 months was observed in the anodal group (59.8%) compared with sham (24.5%). Significant declines were seen in left parietal cortex-left caudal hippocampus connectivity (p = 0.004) and right intraparietal sulcus-right frontal eye fields connectivity (p = 0.039) in the anodal group.

CONCLUSIONS: The intervention was feasible and well tolerated. Findings suggest possible normalization of aberrant or compensatory hyperconnectivity in MCI. Larger studies are needed.Clinical Trial Number: NCT04246164.},
}

@article {pmid42877397,
year = {2026},
author = {Yano, K and Nagata, T and Nakajima, S and Kito, S and Shinagawa, S},
title = {The trajectory of delusions in patients with Alzheimer's disease receiving pharmacological treatment: A re-analysis of data from the CATIE-AD trial.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261494480},
pmid = {42877397},
issn = {2542-4823},
abstract = {BACKGROUND: Previous studies have reported decreases in the proportion of patients with delusions and severity of delusions during long-term follow-up in Alzheimer's disease (AD).

OBJECTIVE: The aim of the present study was to explore clinical predictors of the disappearance of delusions in AD patients enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) trial who received pharmacological treatment.

METHODS: We re-analyzed the data of 421 clinic-based patients enrolled in the CATIE-AD trial to examine the association between the disappearance of delusions and relevant factors selected by reference to previous studies at week 12, 24, and 36 of treatment. Generalized Estimating Equations were used to analyze the impact of the assigned medication (mainly atypical antipsychotics), treatment duration, and their interaction on the disappearance of delusions over time.

RESULTS: The proportion of patients with delusions (PWD) gradually decreased to approximately 50% over the 36-week treatment period; however, no significant differences in the baseline variables were identified between the PWD and patients without delusions (POD) at any of the follow-up time-points (weeks 12, 24, or 36). Furthermore, the treatment duration was found to contribute significantly to the disappearance of delusions over time (conversion from PWD at baseline to POD at subsequent follow-up visits), independent of active drug use.

CONCLUSIONS: Disappearance of delusions in AD patients was associated with the interval from the baseline, regardless of the use of active drugs. Insights into the natural course of delusions could guide clinicians toward selecting alternative treatment strategies for patients with AD.},
}

@article {pmid42877407,
year = {2026},
author = {Horowitz, R},
title = {Improving biomarkers of inflammation including phosphorylated tau in a patient with chronic Lyme disease/post-treatment Lyme disease syndrome using dapsone combination therapy: A case study and literature review.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261445434},
pmid = {42877407},
issn = {2542-4823},
abstract = {BACKGROUND: Borrelia burgdorferi, the agent of Lyme disease, has been found to co-localize in Alzheimer's disease autopsy brain tissues with biofilm, amyloid, and phosphorylated tau.

OBJECTIVE: To determine whether dapsone combination therapy (DCT), a biofilm/persister antibiotic regimen with good central nervous system penetration can improve p-tau and peripheral inflammatory markers in a patient with chronic Lyme disease (CLD)/post-treatment Lyme disease syndrome (PTLDs).

METHODS: A 67-year-old female with CLD/PTLDs, and Ehrlichia, Babesia, Bartonella, and Coxiella burnetii had a 15-year history of joint pain with inflammation and mild cognitive impairment despite prior treatment with doxycycline. She was checked for changes in peripheral inflammation, i.e., rheumatoid factors (RFs) and changes in serum p-tau181, p-tau 217, and amyloid-β (Aβ) 42:40 ratios before and after treatment with DCT.

RESULTS: Elevated RFs at 20 IU/mL decreased into normal range three months post treatment accompanied by a decrease in pain with improved flexibility. An initially elevated serum p-tau 217 level in the blood at 0.33 pg/mL (normal range <0.15 pg/mL) prior to using DCT normalized, decreasing to 0.12 pg/mL three months post therapy, while p-tau 181 levels remained within normal limits. Aβ ratios simultaneously improved post DCT increasing from 0.185 pg/mL to 0.216 (normal range >0.170) accompanied by subjective improvements in concentration and recall.

CONCLUSIONS: This is the first case study proving that a short term, biofilm/persister drug regimen, i.e., DCT, can potentially improve peripheral autoantibodies (RFs) and pathological triggers of neuroinflammation (p-tau, Aβ) in a patient with CLD/PTLDs.},
}

@article {pmid42877439,
year = {2026},
author = {Su, CY and Wong, YS and Lee, C and Sung, SF and Wu, CS and Su, YH and Lin, MH and Ong, CT},
title = {Higher thyroid-stimulating hormone level may delay dementia progression in patients without thyroid dysfunction.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261494184},
pmid = {42877439},
issn = {2542-4823},
abstract = {BACKGROUND: Although thyroid dysfunction causes reversible cognitive impairment, the role of thyroid-stimulating hormone (TSH) variation within the normal range in dementia progression remains unclear.

OBJECTIVE: To evaluate the association between baseline euthyroid TSH levels and cognitive decline rate in dementia patients.

METHODS: We conducted a retrospective cohort study using Taiwan's Ditmanson Research Database (2015-2022). Dementia patients with normal thyroid function who initiated anti-dementia medication were included; those with overt thyroid disease, malignancy, or CNS infections were excluded. Baseline TSH (within 180 days prior to treatment) was stratified by the cohort median (1.392 μIU/mL) into Low and High TSH groups. Longitudinal cognitive outcomes were tracked via repeated Mini-Mental State Examination (MMSE) scores over 3 years. Generalized estimating equation (GEE) models evaluated the TSH-cognitive decline association, adjusting for age, sex, baseline MMSE, medication class, and vascular comorbidities.

RESULTS: A total of 402 patients (955 MMSE observations) were analyzed. Baseline characteristics were comparable between groups. In adjusted analyses, the Low TSH group declined by 1.44 MMSE points per year (95% CI: -1.90 to -0.97; p < 0.001). A significant time-by-TSH group interaction (beta = 0.76, 95% CI: 0.17 to 1.34; p = 0.011) indicated a slower annual decline in the High TSH group (-0.68 points/year).

CONCLUSIONS: Among euthyroid dementia patients, higher baseline TSH levels within the reference range were associated with significantly slower cognitive decline. These findings suggest physiological TSH variations may influence neurodegenerative progression, warranting further prospective research to clarify causality.},
}

@article {pmid42877443,
year = {2026},
author = {Lusk, JB and Fitch, KV and Johnson, KG and Liu, A and Lund, JL and Thomas, LE and McDevitt, R and Zhao, A and Whitson, HE and O'Brien, R and Aymes, S and Hammill, BG and Mac Grory, B and Li, F and O'Brien, EC},
title = {Uptake and safety profile of anti-amyloid immunotherapies in routine clinical practice.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261483526},
pmid = {42877443},
issn = {2542-4823},
abstract = {BACKGROUND: Anti-amyloid immunotherapies are approved by the United States Food and Drug Administration for the treatment of Alzheimer's disease; however, the adoption and safety profile of these medications in routine clinical practice have not been described.

OBJECTIVE: To describe the adoption and safety profile of anti-amyloid immunotherapies in routine clinical practice.

METHODS: This was a retrospective observational cohort study using target trial emulation methods. The data source was nationwide electronic health record data from Epic Cosmos. The primary exposure was the first prescription of anti-amyloid immunotherapy versus the active comparator of oral dementia therapy (acetylcholinesterase inhibitor (AChEI) or memantine, selected to minimize bias by baseline health status and disease severity). The primary end point was time to first nontraumatic intracranial hemorrhage (ICH). Propensity score overlap weighting was used to balance baseline demographic and clinical characteristics across treatment groups.

RESULTS: Between July 1, 2023 and January 1, 2025, 2616 patients (median age 74.8 years [IQR 69.8-78.8]; 53.9% female) were prescribed anti-amyloid immunotherapy (with or without AChEI/memantine), and 1,065,192 patients (median age 79.98 [IQR 73.6-85.6], 57.9% female) were prescribed AChEI/memantine alone. In total, 401 patients prescribed anti-amyloid immunotherapy and 274,470 patients prescribed AChEI/memantine were assessed for safety endpoints. Compared with AChEI/memantine, the analysis did not detect a statistically significant association between prescription of anti-amyloid immunotherapy and ICH (owHR 0.73 [95% CI 0.10-5.12]).

CONCLUSIONS: The study did not detect a statistically significant association between prescription of anti-amyloid immunotherapy and ICH. The small treated cohort and low event count yielded imprecise estimates; these findings do not confirm safety and cannot exclude a clinically important increase in risk.},
}

@article {pmid42877463,
year = {2026},
author = {Takahashi, Y and Shiraishi, N and Tsukahara, A and Matsuda, Y and Nishina, T and Yoshikawa, H and Uzu, T and Mori, E},
title = {Symptomatic lobar intracerebral hemorrhage during extended lecanemab treatment: A case report.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261487915},
pmid = {42877463},
issn = {2542-4823},
abstract = {Lecanemab is an anti-amyloid-β protofibril antibody that slows cognitive decline in early Alzheimer's disease. Although amyloid-related imaging abnormalities (ARIA) occur predominantly early in treatment, reports of hemorrhagic events during extended treatment beyond 18 months remain limited. A 77-year-old woman completed a standard 1.5-year lecanemab regimen without ARIA on surveillance MRIs. The day after her 42nd infusion, she acutely developed confusion and incomprehensible speech. MRI revealed a 2.5-cm left parietal subcortical hemorrhage. This case highlights that symptomatic lobar hemorrhage may occur even during extended lecanemab therapy, underscoring the importance of continued safety monitoring during extended treatment.},
}

@article {pmid42877495,
year = {2026},
author = {Cabrera-Martín, MN and Aguiar-Fernández, P and Camacho-Martí, V and Guillén-Valderrama, EF and Jiménez-Bonilla, JF and Lojo-Ramírez, JA and López-Mora, DA and Matías-Guiu, JA and Paredes-Rodríguez, P and Perissinotti, A and Arbizu, J},
title = {Current use and perspectives of PET imaging in Alzheimer's disease: A Spanish national survey.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823261437129},
pmid = {42877495},
issn = {2542-4823},
abstract = {BACKGROUND: Novel therapies for Alzheimer's disease are expected to increase the demand for biomarkers. PET will likely play a central role in patient selection and treatment monitoring, requiring adequate infrastructure and trained professionals.

OBJECTIVE: To assess the current status of Nuclear Medicine departments in Spain regarding organization, expertise, and available infrastructure.

METHODS: We conducted a nationwide survey among Nuclear Medicine departments in Spain.

RESULTS: Respondents averaged 19.8 years of professional experience; 62.0% had specific neuroimaging training and 76.0% reported high confidence in amyloid PET interpretation. Hospitals were mainly public (70.6%) and widely distributed geographically, and 73.0% reported having cognitive impairment units. Following the INVEAT plan, Spain currently has 147 PET scanners, although capacity varies: most centers operate one scanner and five reported having none. Amyloid PET is available in 77.0% of departments, with annual volumes ranging from fewer than 10 to more than 100 studies; 15.0% cannot perform amyloid PET due to regional limitations. Quantification tools are available in 41.3% of centers, although only 15.5% include quantitative metrics in reports, while 66.7% support the use of centiloid standardization. Nearly all respondents anticipate increased indications for amyloid PET (screening 83.7%; monitoring 68.5%) and support multidisciplinary collaboration (89.1% favor Neuroimaging Committees). About half report workforce needs, mainly nuclear medicine physicians (46.2%). Research activity in Alzheimer's disease is expected to increase (95.6%).

CONCLUSIONS: Most departments recognize the key role of amyloid PET for anti-amyloid therapy implementation and anticipate increased demand, highlighting the need to expand availability, implement quantification tools, and strengthen multidisciplinary collaboration.},
}

@article {pmid42877510,
year = {2026},
author = {Abdelkader, MS and Atalah, HN and Mamdouh, A and Ghazal, R and Bakr, M and Salama, M},
title = {Retinal tau imaging and histopathology as emerging Alzheimer's disease biomarkers: A systematic review.},
journal = {Journal of Alzheimer's disease reports},
volume = {10},
number = {},
pages = {25424823251391710},
pmid = {42877510},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition and tau protein aggregation. The retina, as an extension of the central nervous system, has emerged as a promising site for detecting biomarkers of AD.

OBJECTIVE: This systematic review synthesizes the current evidence on retinal tau protein as a diagnostic tool for AD and related tauopathies.

METHODS: This systematic review adhered to PRISMA guidelines, analyzing studies on retinal tau biomarkers, structural changes, and diagnostic imaging techniques. The included studies encompassed molecular investigations, experimental models, and clinical imaging approaches.

RESULTS: Retinal phosphorylated tau (p-tau) and related isoforms were consistently identified as correlating with systemic AD pathology, including Braak staging. Experimental and clinical studies revealed early retinal changes, such as ganglion cell degeneration and blood-retina barrier breakdown, that preceded cognitive decline. Diagnostic advancements, including curcumin fluorescence imaging, ferritin nanocages, and hyperspectral imaging, demonstrated enhanced precision and feasibility for detecting retinal tau and Aβ in vivo and postmortem. These findings suggest that retinal tau serves as a robust biomarker for AD.

CONCLUSIONS: Retinal tau pathology represents a powerful diagnostic tool, providing non-invasive access to early AD pathology. By integrating molecular insights with advanced imaging modalities, retinal biomarkers could enable earlier diagnosis, therapeutic monitoring, and personalized treatment strategies. Future research should focus on longitudinal validation of retinal biomarkers across diverse populations.},
}

@article {pmid42877578,
year = {2026},
author = {Wang, R and Yang, Q and Cao, Z and Zhou, J and Tian, B and Wang, X and Zhang, X and Xiang, Q and Chen, G},
title = {From scavenger to victim: mechanism and treatment of microglial ferroptosis in white matter injury disease.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1859981},
pmid = {42877578},
issn = {1664-3224},
mesh = {*Ferroptosis ; Humans ; *Microglia/metabolism/pathology/immunology ; Animals ; *White Matter/pathology/metabolism/injuries/immunology ; Iron/metabolism ; *Leukoencephalopathies/metabolism/pathology ; Lipid Peroxidation ; Myelin Sheath/metabolism ; },
abstract = {Failure of myelin repair is a shared pathological feature of white matter injury (WMI)-associated diseases, including Alzheimer's disease (AD), vascular dementia (VaD), and multiple sclerosis (MS), but the underlying mechanisms remain incompletely understood. Microglia, the resident innate immune cells of the central nervous system (CNS), contribute to white matter homeostasis by clearing myelin debris and supporting remyelination. Within the iron- and lipid-rich white matter microenvironment, sustained uptake of myelin and oligodendroglial debris may impose phagocytic and metabolic stress on microglia, thereby increasing their susceptibility to ferroptosis, an iron-dependent form of regulated cell death driven by membrane phospholipid peroxidation. This susceptibility is regulated by interconnected mechanisms involving ferritinophagy-associated iron dysregulation, ACSL4/NOX2/15-LOX-related lipid peroxidation, and impaired endogenous ferroptosis-defense systems. Microglial responses are also heterogeneous: disease-associated, demyelination-associated, white matter-associated, lipid-droplet-accumulating, and degenerative microglial programs represent partially overlapping and context-dependent states rather than a proven linear trajectory. In susceptible microglial subsets, ferroptosis or ferroptosis-associated dysfunction may impair debris clearance and trophic support while promoting oxidized lipid accumulation and inflammatory signaling, thereby limiting remyelination. This review summarizes current evidence on the molecular mechanisms, multicellular interactions, microglial states, disease contexts, and therapeutic strategies associated with microglial ferroptosis in WMI. We further propose a functional therapeutic-window framework based on phagocytic competence, iron-lipid handling capacity, antioxidant reserve, and evidence of ferroptotic injury, and discuss major challenges in clinical translation. Overall, current evidence supports microglial ferroptosis as a context-dependent contributor to myelin repair failure rather than a universal determinant.},
}

*Ferroptosis
Humans
*Microglia/metabolism/pathology/immunology
Animals
*White Matter/pathology/metabolism/injuries/immunology
Iron/metabolism
*Leukoencephalopathies/metabolism/pathology
Lipid Peroxidation
Myelin Sheath/metabolism

@article {pmid42877708,
year = {2026},
author = {Li, S and Yu, Y and Cunanan, V and Masaki, K and Ross, GW},
title = {Lifestyle, APOE ε4, amyloid burden, and race/ethnicity differences in cognition, mood, and anxiety among cognitively unimpaired older adults.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70494},
pmid = {42877708},
issn = {2352-8729},
abstract = {INTRODUCTION: We assessed whether lifestyle, race/ethnicity, and apolipoprotein E gene (APOE) ε4 were associated with cognition or mood/anxiety.

METHODS: This secondary cohort analysis used data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) cohort. Cognitively unimpaired adults aged 65 to 85 years (n = 1705) reported baseline lifestyle behaviors (summed as healthy lifestyle index [HLI]). APOE ε4 carrier status and amyloid positron emission tomography were assessed at baseline, while cognitive, anxiety, and depressive outcomes were assessed longitudinally. Associations were tested using mixed-effects models.

RESULTS: Among Non-Hispanic White participants, higher HLI was associated with fewer depressive symptoms, sufficient sleep was associated with smaller ε4-related increases in anxiety, and excessive alcohol use amplified ε4-related cognitive decline. Among participants from other racial/ethnic groups, walking and higher HLI were associated with more favorable anxiety/depression trajectories.

DISCUSSION: Adequate sleep, limited alcohol, walking, and no smoking may support emotional and cognitive health.},
}

@article {pmid42341744,
year = {2026},
author = {Marth, L and Lund, A and Höglinger, G and Levin, J},
title = {[Dementia with Lewy bodies].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {94},
number = {9},
pages = {340-350},
pmid = {42341744},
issn = {1439-3522},
support = {EXC 2145 SyNergy ID 390857198//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Humans ; *Lewy Body Disease/diagnosis/therapy/psychology/pathology/epidemiology ; alpha-Synuclein/metabolism ; Biomarkers ; Lewy Bodies/pathology ; },
abstract = {Dementia with Lewy bodies (DLB) is the second most common neurodegenerative type of dementia after Alzheimer’s disease and belongs to the atypical parkinsonian syndromes. It is characterized by cognitive fluctuations, visual hallucinations, REM sleep behavior disorder, and parkinsonism. Typically, cognitive impairment appears before or within one year after the onset of motor symptoms (“one-year rule”). Neuropathologically, DLB is an α-synucleinopathy with neuronal Lewy bodies, often accompanied by copathologies. Diagnosis is based on clinical McKeith criteria and often supported by imaging biomarkers. Treatment is mainly symptomatic. Disease-modifying therapies are not yet available but are being investigated in clinical trials. The development of biologically defined diagnostic criteria and molecular biomarkers is crucial for future therapeutic studies.},
}

Humans
*Lewy Body Disease/diagnosis/therapy/psychology/pathology/epidemiology
alpha-Synuclein/metabolism
Biomarkers
Lewy Bodies/pathology

@article {pmid42870221,
year = {2026},
author = {Lee, GY and Han, SN},
title = {The Receptor for Advanced Glycation End Products: Regulation and Implications in Metabolic Diseases.},
journal = {IUBMB life},
volume = {78},
number = {10},
pages = {e70137},
doi = {10.1002/iub.70137},
pmid = {42870221},
issn = {1521-6551},
support = {NRF-RS-2024-00353119//National Research Foundation (NRF) of Korea/ ; },
mesh = {Humans ; *Receptor for Advanced Glycation End Products/metabolism/genetics ; Signal Transduction ; Animals ; Glycation End Products, Advanced/metabolism ; *Metabolic Diseases/metabolism ; Alzheimer Disease/metabolism ; },
abstract = {Receptor for advanced glycation end-products (RAGE) was originally identified as a receptor for advanced glycation end-products; however, it can also bind a broader range of damage-associated molecular patterns, including S100 proteins, high mobility group box 1, and amyloid-β. Ligand-induced RAGE activation promotes receptor oligomerization and recruitment of diaphanous-related formin-1, which activates several intracellular cascades, leading to the production of inflammatory mediators and reactive oxygen species. RAGE expression is upregulated in disease-associated tissues, including adipose tissue in diabetes and microglia and neurons in Alzheimer's disease, and the mechanisms by which RAGE activation contributes to pathogenesis are disease-specific. The review summarizes the expression and activation of RAGE, and the potential mechanisms through which RAGE contributes to disease pathogenesis. We further discuss current and emerging strategies for modulating RAGE signaling and highlight their therapeutic potential in the prevention and treatment of RAGE-associated diseases.},
}

Humans
*Receptor for Advanced Glycation End Products/metabolism/genetics
Signal Transduction
Animals
Glycation End Products, Advanced/metabolism
*Metabolic Diseases/metabolism
Alzheimer Disease/metabolism

@article {pmid42870413,
year = {2026},
author = {Saengsomsuan, N and Sangkakit, L},
title = {Low-Volume Superior Trunk and Superficial Cervical Plexus Block With Sedation as the Sole Regional Anesthetic for Proximal Humerus Fracture Fixation in a Patient With Alzheimer Disease.},
journal = {The American journal of case reports},
volume = {27},
number = {},
pages = {e954296},
doi = {10.12659/AJCR.954296},
pmid = {42870413},
issn = {1941-5923},
mesh = {Humans ; Female ; Aged ; *Cervical Plexus Block/methods ; *Fracture Fixation, Internal ; *Alzheimer Disease/complications ; *Shoulder Fractures/surgery/complications ; Bupivacaine/administration & dosage ; Hypnotics and Sedatives ; Geriatric Anesthesia ; Anesthetics, Local/administration & dosage ; },
abstract = {BACKGROUND Proximal humerus open reduction and internal fixation (ORIF) is usually performed under interscalene brachial plexus block (ISB) or general anesthesia (GA). ISB causes ipsilateral phrenic nerve paresis in nearly all patients, and GA may raise the risk of postoperative neurocognitive disorders in elderly patients with cognitive impairment. We report the feasibility of a low-volume regional technique, used as the sole regional anesthetic with sedation, in a patient in whom GA avoidance was desirable. CASE REPORT A 68-year-old woman (American Society of Anesthesiologists physical status II) with Alzheimer's disease underwent ORIF of a closed right proximal humerus fracture via a deltopectoral approach under superior trunk block (STB) with 5 mL of 0.5% bupivacaine, combined with superficial cervical plexus block (SCPB) with 3 mL of 0.5% bupivacaine, totaling 8 mL, with propofol and dexmedetomidine sedation. Surgery lasted 174 minutes without intraoperative rescue analgesia. Heart rate ranged from 48 to 68 beats/min during dexmedetomidine infusion without anticholinergic treatment, and oxygen saturation remained at 100% with spontaneous ventilation preserved. The block provided analgesia for about 12 hours, with pain score 1/10 at rest at 24 hours, and satisfaction 10/10. No clinically evident respiratory compromise, Horner's syndrome, or postoperative delirium was observed, although diaphragmatic and cognitive function were not formally assessed. The patient was discharged on postoperative day 2. CONCLUSIONS In this single patient, low-volume STB combined with SCPB was a feasible sole regional anesthetic technique, supported by sedation, for proximal humerus ORIF, completed without conversion to GA or clinically evident respiratory compromise. Respiratory and cognitive outcomes were clinically uneventful but not formally measured; broader utility remains to be established.},
}

Humans
Female
Aged
*Cervical Plexus Block/methods
*Fracture Fixation, Internal
*Alzheimer Disease/complications
*Shoulder Fractures/surgery/complications
Bupivacaine/administration & dosage
Hypnotics and Sedatives
Geriatric Anesthesia
Anesthetics, Local/administration & dosage

@article {pmid42870580,
year = {2026},
author = {Wang, S and Hu, T and He, M and Qin, M and Hu, Y and Zhao, L and Qin, Z},
title = {Cross-tissue graph attention networks for semi-supervised gene expression prediction.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {5},
pages = {},
pmid = {42870580},
issn = {1477-4054},
mesh = {Graph Neural Networks ; Humans ; *Alzheimer Disease/genetics/metabolism ; *Gene Expression Profiling/methods ; Algorithms ; *Gene Expression ; *Computational Biology/methods ; Brain/metabolism ; },
abstract = {High-throughput biotechnologies have significantly advanced precision medicine by enabling the exploitation of global gene expression patterns to enhance our understanding of disease etiology, progression, and treatment options. However, the tissue-specific nature of gene expression presents a challenge, particularly for less accessible tissues such as the brain, underscoring the need for computational methods to accurately impute gene expression in these critical but hard-to-reach tissues. While several attempts to impute gene expression in tissue-specific contexts have shown promising results, their reliance on regression analysis faces limitations due to the inability to capture complex, nonlinear relationships in gene expression patterns. In contrast, modern machine learning techniques, particularly graph neural networks, have demonstrated superior performance by efficiently modeling the intricate interactions among genes across different tissues. Therefore, we introduce gene expression imputation with graph attention networks (gemGAT), a novel approach leveraging GATs to enhance gene expression prediction across different tissues. gemGAT distinguishes itself by predicting the expression of all genes simultaneously, utilizing the full spectrum of genomic data to account for gene coexpressions and nonlinear relationships. Validated through extensive experiments with Genotype-Tissue Expression data and a case study from the Alzheimer's Disease Neuroimaging Initiative, gemGAT demonstrates superior performance over existing methods by efficiently capturing nonlinear gene coexpressions. This advancement underscores gemGAT's potential to significantly contribute to precision medicine, showcasing its utility in advancing our understanding of gene expression in less accessible tissues.},
}

Graph Neural Networks
Humans
*Alzheimer Disease/genetics/metabolism
*Gene Expression Profiling/methods
Algorithms
*Gene Expression
*Computational Biology/methods
Brain/metabolism

@article {pmid42870749,
year = {2026},
author = {Vossberg, DAF and Rolfes, V and Fangerau, H and Haupt, M},
title = {Medical Decision-Making Capacity in Early-Stage Alzheimer Patients: Comparison With Healthy Controls and Benefit of Assistive Information.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {6},
pages = {e70227},
pmid = {42870749},
issn = {1479-8301},
support = {2020-1061//Alzheimer Society of Germany (Deutsche Alzheimer Gesellschaft)/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis ; Female ; Male ; *Decision Making ; Aged ; *Mental Competency/psychology ; *Informed Consent/psychology ; Aged, 80 and over ; Case-Control Studies ; Neuropsychological Tests ; *Audiovisual Aids ; },
abstract = {BACKGROUND: Early-stage Alzheimer Disease (AD) may lead to restricted decision-making capacity and without standardized instruments, there is great variability in determining patients' ability to give consent. This study aimed to assess decision-making capacity of AD patients in comparison to a healthy control group and investigated the usefulness of visual aids.

METHODS: A group of 30 ad patients and 30 healthy controls were compared using the MacArthur Competence Assessment Tool for Treatment (MacCAT-T). Additionally, we implemented a modified version of the MacCAT-T with visual aids.

RESULTS: Results revealed a significant difference in the MacCAT-T domain of Understanding between the AD and control group after adjustment for age, sex, and education. No significant differences were found for Appreciation, Reasoning, or Expression of Choice. Adding visual aids led to no significant improvements.

CONCLUSIONS: Standardized assessments can be valuable tools for determining the decision-making capacity of patients with early-stage AD. The efficacy of visual aids should be further investigated.},
}

Humans
*Alzheimer Disease/psychology/diagnosis
Female
Male
*Decision Making
Aged
*Mental Competency/psychology
*Informed Consent/psychology
Aged, 80 and over
Case-Control Studies
Neuropsychological Tests
*Audiovisual Aids

@article {pmid42872064,
year = {2026},
author = {Cai, W and Yi, Y and Zeng, R and Yin, Y and Zhao, J and Zhang, J and Fu, G and Xu, H},
title = {HMGB1 functional plasticity in neurodegenerative diseases and its translational implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1928641},
pmid = {42872064},
issn = {1664-3224},
mesh = {Humans ; *HMGB1 Protein/metabolism/genetics ; *Neurodegenerative Diseases/metabolism ; Animals ; Translational Research, Biomedical ; Signal Transduction ; Alarmins/metabolism ; Biomarkers ; },
abstract = {High mobility group box 1 (HMGB1) is a chromatin-associated protein that can be redistributed and released during cellular stress, when it acts as an extracellular alarmin within the broader family of damage-associated molecular patterns (DAMPs). Its functions depend on subcellular localization, redox and post-translational modification state, cellular source, mode of release, and molecular partners. This critical narrative review examines how these variables shape HMGB1 biology in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar ataxias (SCAs), frontotemporal dementia (FTD), and related disorders, and considers their implications for biomarker and therapeutic development. Intracellular HMGB1 contributes to chromatin organization, DNA repair, mitochondrial genome maintenance, and proteostasis. After redistribution and release, extracellular HMGB1 signals through receptors including the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), interacts with disease-associated proteins, and links proteostatic stress with glial activation, neuronal dysfunction, and blood-brain barrier impairment. Across disease models, two recurrent patterns emerge: loss or sequestration of intracellular HMGB1 in models of polyglutamine disorders, including HD and SCAs, and extracellular HMGB1 signaling as a progression-associated inflammatory amplifier in AD, PD, and ALS models. Central-peripheral inflammatory communication and cell-specific HMGB1 release further shape these responses. Clinical studies have associated total HMGB1 or anti-HMGB1 autoantibodies with clinical features, but current assays do not resolve redox form, cellular source, or biological activity. Most therapeutic studies remain preclinical, while available human intervention studies involve drugs with multiple molecular actions. Clinical translation requires redox-resolved and standardized assays, longitudinal human sampling, compartment- and cell-specific causal studies, and interventions with documented target engagement, central nervous system exposure, and long-term safety. HMGB1 is best understood as a context-dependent mediator rather than a uniformly pathogenic factor or a single treatment target.},
}

Humans
*HMGB1 Protein/metabolism/genetics
*Neurodegenerative Diseases/metabolism
Animals
Translational Research, Biomedical
Signal Transduction
Alarmins/metabolism
Biomarkers

@article {pmid42872207,
year = {2026},
author = {Wang, M and VanderVeen, B and Xu, ZA and Xu, Y and Mintzer, J and Murphy, A and Zhang, Q and Xu, P},
title = {Reverse the progression of Alzheimer's disease through Nano-ERASER-based adult neuroregeneration.},
journal = {Cell biomaterials},
volume = {},
number = {},
pages = {},
pmid = {42872207},
issn = {3050-5623},
support = {P30 GM154632/GM/NIGMS NIH HHS/United States ; R01 AG054839/AG/NIA NIH HHS/United States ; R01 CA263747/CA/NCI NIH HHS/United States ; R41 AG087769/AG/NIA NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) remains irreversible largely because the adult brain cannot replace lost neurons. Here, we present a Nano-ERASER-based Trim-Away system (TN-PTBP1) that enables adult neuroregeneration in the AD brain, offering a new strategy to counteract AD progression. TN-PTBP1 penetrates the blood-brain barrier, delivers anti-PTBP1 antibodies into astrocytes, and triggers rapid TRIM21-mediated PTBP1 degradation. This non-genomic protein depletion induces astrocyte-to-neuron conversion, generates functional neurons in vitro and in human brain organoids, and restores hippocampal neurogenesis in AD mice. Importantly, TN-PTBP1 treatment significantly improves cognition, learning, and memory, demonstrating true functional reversal of AD-associated deficits. By resolving the long-standing controversy surrounding PTBP1 reprogramming and establishing a translational biomaterials-based platform for in situ neuronal regeneration, this work introduces a transformative therapeutic paradigm aimed not only at slowing AD but at rebuilding the neuronal circuitry it destroys.},
}

@article {pmid42872450,
year = {2026},
author = {Kang, K},
title = {Bilateral Lower Extremity Edema During Donepezil Treatment: A Case Report.},
journal = {Current drug safety},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115748863527540260928113823},
pmid = {42872450},
issn = {2212-3911},
abstract = {Introduction/ Background: Acute bilateral lower-extremity edema is uncommon and often results from medication side effects, acute heart failure, nephrotic syndrome, or bilateral deep vein thrombosis. Drugs such as dihydropyridine calcium channel blockers, corticosteroids, thiazolidinediones, and nonsteroidal anti-inflammatory agents are known to cause edema. Donepezil, a widely used acetylcholinesterase inhibitor for Alzheimer's disease, has not been previously linked to leg edema. Recognizing rare adverse reactions is essential for patient safety, as edema may indicate serious conditions. Case Presentation: A 75-year-old woman with Alzheimer's disease developed bilateral pitting lower leg edema six months after starting treatment with donepezil. She had no history of cardiac, renal, hepatic, or venous diseases. Laboratory tests, electrocardiography, chest X-ray, and computed tomography venogram were normal, except for mild anemia and a slightly reduced estimated glomerular filtration rate. The edema resolved three weeks after discontinuation and did not recur after the administration of rivastigmine. Conclusion: The temporal association and resolution upon drug cessation suggest a probable association. Possible mechanisms may include cholinergic-induced vasodilation, which increases capillary permeability.},
}

@article {pmid42872643,
year = {2026},
author = {Patel, R and Sinha, S and Shukla, KS and Singh, B and Ved, A and Kumar, A and Yadav, N and Singh, V},
title = {Therapeutic Significance of Natural vs. Synthetic Coumarins in Alzheimer's Disease.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575482030261005073306},
pmid = {42872643},
issn = {1875-5607},
abstract = {INTRODUCTION/OBJECTIVE: Coumarin, a naturally occurring aromatic compound bearing a benzopyrone scaffold, represents a versatile motif in synthetic drug design. Recent therapeutic developments have highlighted its potential as a privileged pharmacophore for neurodegenerative disorders (NDs), with particular efficacy targeting Alzheimer's disease (AD). This study presents a critical, comparative review of natural versus synthetic coumarins, evaluating their neuroprotective mechanisms across various preclinical, non-transgenic models of sporadic Alzheimer's disease (sAD).

METHODS: Natural coumarins (e.g., umbelliferone, esculetin, and scopoletin) exert potent antioxidant, anti-inflammatory, and moderate enzyme-inhibitory activities, particularly against acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation. These phytochemicals attenuate neurodegeneration by modulating oxidative stress and neuroinflammatory pathways across various cellular and rodent models, including 5xFAD mice, as well as streptozotocin (STZ)-and scopolamine (SCOP)- induced Alzheimer's disease (AD) rat models. However, their clinical utility remains constrained by poor bioavailability and modest potency. To address these limitations, synthetic coumarin derivatives, including coumarin-pyrrolidine, coumarin-triazole, coumarin-chalcone, and coumarin-donepezil hybrids, as well as hydroxycoumarins, have been developed. These heterocyclic hybrid architectures exhibit superior therapeutic potency, enhanced blood-brain barrier (BBB) permeability, and synergistic inhibition of core pathological targets, including AChE activity and Aβ aggregation.

RESULT: Both in vivo preclinical models and in silico docking simulations substantiate the neuroprotective capacity of coumarin-based frameworks, demonstrating substantial cognitive rescue, restored synaptic plasticity, and favorable safety margins. Moving beyond the baseline safety of naturally derived coumarins, structural optimization and hybrid design strategies serve as a compelling framework for developing potent, multi-target therapeutics for neurodegenerative diseases.

DISCUSSION: According to the review, Alzheimer's disease treatment is shifting from natural coumarins to multi-target-directed ligands (MTDLs) because natural compounds, such as esculetin, scopoletin, and daphnetin, are often limited by narrow target specificity and lower potency than synthetic coumarin derivatives.

CONCLUSION: Herein, the authors review the biological activities of natural coumarins and their synthetic analogs as potential therapeutics for Alzheimer's disease (AD). This study systematically compared and evaluated the therapeutic efficacy and structural scaffold variations of both natural and synthetic derivatives. To support their translational potential, this study also summarizes current ADMET profiles and pharmacokinetic evaluations, which represent key prerequisites for clinical advancement.},
}

@article {pmid42872646,
year = {2026},
author = {Budak Savaş, A and Yeşilyurt, F and Hacimuftuoglu, A},
title = {From Hypothesis to Clinical Validation: A Bibliometric Mapping of Immunotherapy for Neurodegenerative Proteinopathies (2000-2025).},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273531307261012100737},
pmid = {42872646},
issn = {1996-3181},
abstract = {INTRODUCTION/OBJECTIVE: For twenty-five years, despite persistent challenges, the field of neurodegenerative disease has remained committed to a single hypothesis: targeting the immune system directly against misfolded proteins accumulating in the brain. Today, this approach has produced a clinical counterpart, with three monoclonal antibodies now approved, although the field is still progressing toward clinical validation. However, the research lines, countries, institutions, and journals through which this point was reached, and how far that validation has actually progressed, have remained largely unexamined.

METHODS: This study analyzes 9,863 articles published between 2000 and 2025 using bibliometric methods to map the field's intellectual structure, productivity patterns, and the thematic evolution shaped around four turning points.

RESULTS: The findings reveal a nonlinear trajectory. Annual output rose from a steady pace in the early 2000s to a sudden surge after 2019, exceeding 900 publications per year. Research output is heavily concentrated in the United States, while impact is concentrated among a small number of core journals and prolific authors. Only 47 journals account for one-third of the literature, and roughly four out of five authors have contributed only a single publication to the field. While the amyloid hypothesis continues to rest on strong genetic foundations, which protein species is actually neurotoxic, soluble oligomers or deposited plaques, remains an open question, and this keeps alive the debate over what clinical trials are truly measuring. The safety of approved drugs, particularly ARIA-related imaging abnormalities, and the challenge of delivering treatment across the blood-brain barrier stand out as fronts the field has yet to overcome.

DISCUSSION: Perhaps the most notable signal is that this accumulated progress now appears to be extending beyond Alzheimer's disease: thematic patterns suggest the same immunotherapeutic logic is beginning to extend toward Parkinson's disease and other proteinopathies.

CONCLUSION: The study presents, within a single framework, the critical periods the field has passed through, who has led this journey, and which questions remain unanswered.},
}

@article {pmid42872652,
year = {2026},
author = {Watson, D and Neam, MG and Stafford, M and Bouchard, C and Ranney, V and Werner, S},
title = {Transitioning from Clinical Trial to Clinical Practice for Long-Term Lecanemab Treatment in Early Alzheimer's Disease: Perspectives from a Cohort Study from the Alzheimer's Research and Treatment Center.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050525938260923072703},
pmid = {42872652},
issn = {1875-5828},
abstract = {INTRODUCTION/BACKGROUND: Lecanemab, an anti-amyloid monoclonal antibody, significantly reduces amyloid markers and slows clinical decline in early Alzheimer's disease (AD) clinical trials. We assessed our single-center experience with lecanemab, including evaluating efficacy and safety data as well as patient-reported outcomes of individuals from our single center treated with intravenous or subcutaneous lecanemab.

MATERIALS AND METHODS: We conducted a single-center, nested cohort study of early AD subjects on lecanemab (intravenous or subcutaneous) at our center. Participants had been initiated on lecanemab therapy as part of lecanemab Study 201 or Clarity AD, and then continued lecanemab treatment in our center. Data collection included patient demographic characteristics, efficacy (eg, CDR-SB), safety, and patient-reported outcomes from surveys.

RESULTS: At our center, 136 people were randomized to receive either lecanemab or placebo in either lecanemab Study 201 (lecanemab:53; placebo:16) or Clarity AD (lecanemab:37; placebo:30). Patients receiving lecanemab were more likely to have higher rates of stable or improved disease across efficacy assessments relative to placebo. There were no new long-term safety signals, and the most common adverse events for lecanemab patients were infusion-related reactions (36.2%), ARIA-H (25.9%), and ARIA-E (13.8%). Survey responses demonstrated high satisfaction with the subcutaneous lecanemab administration, including with treatment satisfaction (97%) and convenience (97%). All patients preferred subcutaneous over IV dosing, citing quickness, ease, and comfort.

DISCUSSION: Our single-center experience with long-term lecanemab treatment was similar to that observed in clinical trials.

CONCLUSION: The subcutaneous lecanemab formulation was highly preferred by patients and care partners, with feedback highlighting reduced treatment burden and strong acceptability.},
}

@article {pmid42872679,
year = {2026},
author = {Li, M and Lv, S and Cui, L and Fang, S},
title = {Tetrachloro-1,4-benzoquinone Exerts Neurotoxicity through Neuroinflammation and the TLR4 Signaling Pathway, which is a Risk Factor for Alzheimer's Disease: An Integrated Network and Mendelian Randomization Analysis.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050502048260925094031},
pmid = {42872679},
issn = {1875-5828},
abstract = {INTRODUCTION: Research has found that the disinfection byproduct Tetrachloro-1,4- Benzoquinone (TCBQ) in drinking water increases the risk of Alzheimer's Disease (AD). However, the mechanism by which TCBQ increases the risk of AD remains unclear.

METHODS: This study employs a comprehensive approach that includes network toxicology (PPI network, hub genes, KEGG analysis), Mendelian randomization, computational simulations (molecular docking and dynamics), and cellular experiments to systematically elucidate the neurotoxic mechanisms of TCBQ.

RESULTS: Key findings indicate that TCBQ induces neurotoxicity by activating the Toll-like receptor signaling pathway, AD, and the apoptosis pathway. All ligand-receptor docking energies are recorded at ≤ -1.8 kcal/mol, suggesting that TCBQ demonstrates a stable interaction with the targets. Molecular simulations confirm that TCBQ tightly binds to targets such as Caspase3 and TLR4. Mendelian randomization found that XDH, FABP3, IMPDH1, ACBD7, and CASP3 are common targets and play a potential role in AD. Immunofluorescence experiments revealed that APP expression increased after TCBQ treatment. Cellular experiments verified that TCBQ significantly upregulates the expression of inflammation- and apoptosis-related proteins, including IL-1B, MyD88, NFκB, TLR4, Cleaved-Caspase3, and Cyt C, leading to neuronal cell death. Notably, the TLR4 inhibitor effectively reversed the expression of these proteins and alleviated cell death.

DISCUSSION: The discussion indicates that TCBQ induces neurotoxicity by activating the TLR4 pathway and apoptotic signals, and Caspase3 is a potential co-target. TLR4 inhibitors can reverse protein alterations and cell death, suggesting that intervention in this pathway may alleviate TCBQrelated nerve damage.

CONCLUSION: Our research provides a theoretical basis for the clinical assessment of potential neurotoxicity risks in populations exposed to TCBQ.},
}